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WO2018137655A1 - Pyrrolo-pyridines n-oxide derivative, preparation method therefor, and application thereof - Google Patents

Pyrrolo-pyridines n-oxide derivative, preparation method therefor, and application thereof Download PDF

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Publication number
WO2018137655A1
WO2018137655A1 PCT/CN2018/073989 CN2018073989W WO2018137655A1 WO 2018137655 A1 WO2018137655 A1 WO 2018137655A1 CN 2018073989 W CN2018073989 W CN 2018073989W WO 2018137655 A1 WO2018137655 A1 WO 2018137655A1
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Prior art keywords
group
methyl
alkyl
pyrrolo
phenyl
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PCT/CN2018/073989
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French (fr)
Chinese (zh)
Inventor
野国中
李凯龙
黄志强
刘磊
包如迪
Original Assignee
江苏豪森药业集团有限公司
上海翰森生物医药科技有限公司
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Priority to CN201880006296.4A priority Critical patent/CN110198941B/en
Publication of WO2018137655A1 publication Critical patent/WO2018137655A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicine and relates to pyrrolopyridinium N-oxidized derivatives, a preparation method thereof and application of the pharmaceutical composition in medical research, and the invention discloses as a BRD4 inhibitor in treating cancer, inflammation, chronic liver disease and diabetes.
  • Tumors are one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries.
  • the incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3% to 5%.
  • Ageing, urbanization, industrialization and lifestyle changes In China's hospital drug market, the sales scale of anti-cancer drugs has been growing steadily in recent years. In 2012, it reached 66.42 billion yuan, an increase of 13.07% year-on-year. It is expected that by 2017, the market size of anti-cancer drugs will reach 105.57 billion yuan. The year-on-year growth was 7.57%.
  • Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy. The natural defense mechanism of the host or the naturally occurring highly targeted substance is obtained to obtain an anti-tumor effect.
  • Bromostructured protein 4 (BRD4) is a member of the bromodomain and extraterminal domain (BET) family, and BRD4 recruits different transcriptional regulators such as Mediator, positive transcription elongation factor b (positive transcription elongation factor b) , P-TEFb) to regulate the expression of the target gene.
  • BET bromodomain and extraterminal domain
  • P-TEFb transcriptional regulators
  • BRD4 shRNA or BET inhibitor can induce cell cycle arrest, apoptosis and cell differentiation of the above tumors, and exhibits strong antitumor activity.
  • BRD4 inhibitors have good application prospects in the pharmaceutical industry as pharmaceuticals. Currently, there are no listed drugs. In order to achieve better therapeutic effects and meet market demand, we hope to develop a new generation of highly efficient and low toxicity selective BRD4. Inhibitor.
  • the object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture form, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) has the following structure:
  • X, Y are each independently selected from the group consisting of a bond, N, O, -NR 5 -, -(CR 6 R 7 ) x -, and -(CR 6 R 7 ) x N(R 5 ) y -;
  • Z is selected from -NR 5 -, O and -O(CR 6 R 7 ) x -;
  • Ring A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 1 is selected from the group consisting of alkyl, cycloalkyl and alkenyl; wherein said alkyl, alkenyl and cycloalkyl are optionally further selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy Substituted by one or more substituents of a group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an olefin, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C( O) R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from alkyl, haloalkanes Base,
  • R 3 is selected from the group consisting of a non-existent hydrogen atom, an alkyl group, a halogenated alkyl group, an alkene group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a hetero group.
  • R 2 and R 3 are bonded to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl are optionally further selected from the group consisting of alkyl, haloalkyl, alkene, alkoxy, haloalkoxy , halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S (O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m
  • R 10 Substituted by
  • R 2 and R 3 are each independently bonded to R 6 , R 7 or R 5 on the X group to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl group are optionally further Selected from alkyl, haloalkyl, olefin, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 And one or more substituents in -NR 9 S(O) m R 10 are substituted;
  • R 4 is independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, Heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -(CH 2 ) t NR 9 R 10 , -(CH 2 ) t C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Further optionally, it is selected
  • R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group.
  • R 6 and R 7 may form a cycloalkyl or heterocyclic group, which is optionally further selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halogen , amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m
  • R 10 Replace
  • R 8 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, Haloalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halo, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy Base, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R Substituting one
  • R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group And a heterocyclic group, an aryl group and a heteroaryl group are further selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group. And substituted with one or more substituents in the heteroaryl;
  • n is an integer of 0, 1, or 2;
  • n is an integer of 0, 1, 2, 3, 4 or 5;
  • t is an integer of 0, 1, 2, 3, 4 or 5;
  • x is an integer of 0, 1, 2, 3 or 4;
  • y is an integer of 0 or 1.
  • the compound of the formula (I) is a compound of the formula (II):
  • B is selected from CH and N;
  • R 1 to R 4 , Z, X, Y and n are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (III):
  • B is selected from CH and N;
  • R 1 , R 2 , R 4 , Z, X and n are as defined in the formula (I).
  • the compound of the formula (I) is a compound of the formula (IV):
  • Z is selected from NH and O
  • B is selected from CH and N;
  • Ring C is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halogen, amino, Substituted by one or more substituents of a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
  • z is an integer of 0, 1, 2 or 3;
  • R 1 , R 2 , R 4 , X and n are as defined in the formula (I).
  • the compound represented by the formula (IV) is a compound represented by the formula (VA) or (VB):
  • Z is selected from NH and O
  • X is selected from the group consisting of a bond, NH and -CR 6 R 7 -;
  • R 4 is selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 3-6 cycloalkyl group, -(CH 2 ) t NR 9 R 10 and -(CH 2 ) t C(O)NR 9 R 10 ;
  • R 2 is selected from C 1-6 alkyl, halo C 1-6 alkyl, -NR 9 R 10 , C 3-6 cycloalkyl or 5-6 membered heteroaryl; wherein said C 1-6 The alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are further optionally selected from C 1-6 alkyl groups, halogenated C 1-6 alkyl groups, halogen Substituting one or more substituents of an amino group, a cyano group and a hydroxyl group;
  • R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group
  • R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group
  • n, t is as defined in the general formula (I).
  • the compound of the formula (IV) is a compound of the formula (VIA) or (VIB):
  • Z is selected from NH and O
  • X is selected from the group consisting of a bond, NH and -CR 6 R 7 -;
  • R C is independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 3-6 cycloalkyl group, a ( CH 2 ) t NR 9 R 10 or -(CH 2 ) t C(O)NR 9 R 10 ;
  • R 2 is selected from C 1-6 alkyl, halo C 1-6 alkyl, -NR 9 R 10 , C 3-6 cycloalkyl and 5-6 membered heteroaryl; wherein said C 1-6 The alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are further optionally selected from C 1-6 alkyl groups, halogenated C 1-6 alkyl groups, halogen Substituting one or more substituents of an amino group, a cyano group and a hydroxyl group;
  • R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group
  • R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group
  • R 1 is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl and C 3-8 cycloalkyl; C 1-6 alkyl, C 2-6 alkenyl or C 3-6 cycloalkyl; more preferably C 1-3 alkyl, C 2-3 alkenyl or C 3-6 cycloalkyl; most preferably methyl .
  • the compound of the formula, wherein R 2 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and a -6 membered heteroaryl group, wherein said C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are optionally further selected from C 1 Substituted by one or more substituents of -6 alkyl, halo C 1-6 alkyl, halogen, amino, cyano and hydroxy; preferably C 1-6 alkyl, halo C 1-6 alkyl or C 3-6 cycloalkyl; more preferably C 1-3 alkyl, halo C 1-3 alkyl or C 3-6 cycloalkyl, most preferably methyl, ethyl, isopropyl, cyclopropyl, Cyclobutyl,
  • the compound of formula (I) is selected from the group consisting of:
  • a tautomer a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • R 1 to R 4 , ring A, Z, X, Y and n are as defined in the formula (I).
  • a method for preparing a compound of the formula (I) comprises the following steps:
  • the compound of the formula (V) is oxidized by an oxidizing agent to give a compound of the formula (I);
  • the oxidizing agent is preferably m-chloroperoxybenzoic acid;
  • R 1 to R 4 , ring A, Z, X, Y and n are as defined in the formula (I);
  • a method for preparing a compound represented by the formula (VA) comprises the following steps:
  • the compound of the formula (VAA) is oxidized by an oxidizing agent to give a compound of the formula (VA);
  • the oxidizing agent is preferably m-chloroperoxybenzoic acid;
  • R 2 , R 4 , Z, X and n are as defined in the formula (VA);
  • a method for preparing a compound represented by the formula (VB) comprises the following steps:
  • the compound of the formula (VBB) is oxidized by an oxidizing agent to give a compound of the formula (VB);
  • the oxidizing agent is preferably m-chloroperoxybenzoic acid;
  • R 2 , R 4 , Z, X and n are as defined in the formula (VB);
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention also relates to a process for the preparation of the above pharmaceutical composition which comprises the compounds of the formulas or their tautomers, meso, racemates, enantiomers, non-pairs
  • the conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof is admixed with a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the preparation of a medicament for the prophylaxis and/or treatment of a medicament for the treatment of cancer, inflammation, AIDS as a BRD4 inhibitor. .
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a BRD4 inhibitor drug.
  • the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS.
  • the present invention also relates to a method of treating a disease preventing and/or treating a BRD4-mediated pathological feature comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof. , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same
  • Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • This method shows outstanding efficacy and fewer side effects.
  • Another aspect of the invention relates to a method of treating inflammation comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  • This method shows outstanding efficacy and fewer side effects.
  • Another aspect of the invention relates to a method of treating chronic liver disease, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, or an external Racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof.
  • This method shows outstanding efficacy and fewer side effects.
  • the cancer of the present invention may be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymph.
  • Tumor, myeloma and non-small cell lung cancer said chronic liver disease is selected from the group consisting of: primary sclerosis (PBC), cerebral xanthoma (CTX), primary sclerosing cholecystitis (PSC), drug-induced Cholestasis, intrahepatic cholestasis of pregnancy, parenteral absorption-related cholestasis (PNAC), bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD) ), nonalcoholic steatohepatitis (NASH), liver graft-related graft-versus-host disease, live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren Syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatos
  • alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms.
  • the alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
  • the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • an alkane Base alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, hetero
  • alkylene means that one hydrogen atom of the alkyl group is further substituted, for example, "methylene” refers to -CH 2 -, "ethylene” refers to -(CH 2 ) 2 -, "propylene” Refers to -(CH 2 ) 3 -, "butylene” means -(CH 2 ) 4 - and the like.
  • alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like.
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
  • a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine.
  • the base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably tetrahydrofuranyl and pyranyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
  • the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • fused heterocyclic groups include:
  • the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
  • the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl,
  • a pyrimidinyl group, a thiadiazole, a pyrazinyl group or the like is preferably an imidazolyl group, a pyrazolyl group or a pyrimidinyl group, or a thiazolyl group; and a pyrimidyl group is more preferred.
  • the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring
  • the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
  • haloalkyl refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
  • haloalkoxy refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
  • hydroxy refers to an -OH group.
  • halogen means fluoro, chloro, bromo or iodo.
  • amino means -NH 2.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl is as defined above.
  • X is selected from A, B, or C
  • X is selected from A, B, and C
  • X is A, B, or C
  • X is A, B, and C
  • the hydrogen atom of the present invention may be substituted by its isotope ruthenium, and any of the hydrogen atoms in the examples of the present invention may also be substituted by a ruthenium atom.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
  • DMSO-d 6 dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • TMS Methylsilane
  • chemical shifts are given in units of 10 -6 (ppm).
  • the measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • ESI FINNIGAN LCQAd
  • the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specification for separation and purification of thin layer chromatography is 0.4mm. ⁇ 0.5mm silica gel plate.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
  • An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
  • the solution in the reaction means an aqueous solution unless otherwise specified.
  • the temperature of the reaction was room temperature unless otherwise specified.
  • Room temperature is the most suitable reaction temperature, and the temperature range is from 20 ° C to 30 ° C.
  • the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
  • TLC thin layer chromatography
  • the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
  • the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, acetic acid Ethyl ester and dichloromethane system, D: petroleum ether and ethyl acetate system, E: ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acid or alkali may be added. The reagents and the like are adjusted.
  • Second step Preparation of (6-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone
  • the third step preparation of 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine
  • the fourth step preparation of 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene
  • Step 7 N-(4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Preparation of phenyl) ethanesulfonamide
  • N-(3-Bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide 500 mg, 1.28 mmol
  • 4,4,4',4',5,5,5' , 5'-octamethyl-2,2'-linked (1,3,2-dioxaborolan) (648 mg, 2.55 mmol)
  • 1,3,5,7-tetramethyl-6-phenyl -2,4,8-trioxa-6-phosphoryladamantane 37 mg, 0.128 mmol
  • tris(dibenzylideneacetone)dipalladium 35 mg, 0.038 mmol
  • potassium acetate 275 mg, 2.82 mmol
  • reaction solution was reacted at 80 ° C for 12 hours under nitrogen atmosphere, and then reacted at 105 ° C for 5 hours.
  • the reaction solution was evaporated to dryness and then purified (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -(4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)
  • a mixture of ethanesulfonamide 500 mg was used directly in the next step.
  • Step 8 N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Preparation of sulfonamide
  • reaction solution was subjected to microwave reaction at 120 ° C for 0.5 hour under a nitrogen atmosphere.
  • Step 9 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Preparation of pyridine-7-oxide
  • EtOAc EtOAc: EtOAc: EtOAc: 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide (12 mg, yield 19%).
  • 6-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (17.0 g, 74 mmol) was dissolved in N,N-dimethylformamide (50 mL).
  • Sodium hydride (5.9 g, 147 mmol) was added portionwise to the above solution, and after stirring for 10 minutes at 0 ° C, 4-methylsulfonyl chloride (18.3 g, 96 mmol) was dissolved in N,N-dimethyl
  • a solution of the amide (30 mL) was slowly added to the above reaction solution. After stirring at room temperature for 1 hour, the reaction was completed by LC/MS.
  • reaction solution was poured into ice water (500 mL) and stirred, a large white solid was precipitated, filtered, and the filter cake was washed with water (100 mL) and dried to give 6-bromo-4-chloro-1-toluenesulfonyl-1H-pyrrole And [2,3-b]pyridine (27.0 g, yield 94.7%).
  • the third step preparation of 4-chloro-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine
  • 6-Bromo-4-chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (15.5 g, 40 mmol) was dissolved in tetrahydrofuran (150 mL) and [1,1'-bis (two) Phenylphosphino)ferrocene]palladium dichloride (1.46 g, 2 mmol), replacing nitrogen, adding dimethyl zinc (20 mL, 1 M solution in toluene) under ice bath, heating to 70 ° C after completion of the addition. The reaction was carried out overnight, and the reaction was completed by LC/MS.
  • Step 6 N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4- Preparation of phenyl)phenylpropanesulfonamide
  • Step 8 4-(5-(Cyclopropanesulfonylamino)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Preparation of pyridine-7-oxide
  • N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)cyclopropanesulfonamide (40 mg, 0.087 mmol) was dissolved in THF (0.5 mL). m. m. m.
  • N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene Starting from -3,5-dimethylisoxazole-4-sulfonamide as a starting material, referring to the seventh step of Example 2, the compound N-(4-(2,4-difluorophenoxy)-3- (6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-3,5-dimethylisoxazole-4-sulfonamide (70 mg, yield 83%) .
  • the third step 4-(2-(2,4-difluorophenoxy)-5-((3,5-dimethylisoxazole)-4-sulfonylamino)phenyl)-6-A Preparation of 7-oxidation of yl-1H-pyrrolo[2,3-b]pyridine
  • N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene The propane-2-sulfonamide was used as a starting material. Referring to the seventh step of Example 2, the compound N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrole was obtained. [2,3-b]pyridin-4-yl)phenyl)propane-2-sulfonamide (69 mg, yield 84%).
  • N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)propane-2- Sulfonamide was used as the starting material.
  • EtOAc 2,4-Difluorophenoxy-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2,2,2-trifluoroethane 1-sulfonamide (0.06 g) was used directly in the next reaction.
  • the third step 4-(2-(2,4-difluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl-1H -pyrrolo[2,3-b]pyridine-7-oxide
  • Step 6 4-(2-(4-Bromo-2-fluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b Preparation of pyridine-7-oxide
  • N-(4-(4-Bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)ethanesulfonamide 70 mg, 0.14 mmol was dissolved in tetrahydrofuran (2 mL), and m-chloroperoxybenzoic acid (42 mg, 0.21 mmol) was added and stirred at room temperature for 30 min. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium sulfate (30 mL ⁇ 2) and then washed with brine (30 mL).
  • Second step 4-(2-(4-bromo-2-fluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl- Preparation of 1H-pyrrolo[2,3-b]pyridine-7-oxide
  • N-(3-Bromo-4-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)ethanesulfonamide (0.4 g, 1.1 mmol), 6-methyl-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.5g , 1.3 mmol), potassium carbonate (350 mg, 2.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (80 mg, 0.1 mmol) dissolved in 1,4 dioxane Ring (10 mL) and water (2 mL) were stirred and stirred at 90 ° C for 2 hr under nitrogen.
  • Step 5 N-(3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl) Preparation of oxo)phenyl)ethanesulfonamide
  • Step 6 4-(5-(ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine-7-oxide
  • Phenyl)ethanesulfonamide 100 mg, 0.23 mmol
  • m-chloroperoxybenzoic acid 95 mg, 0.46 mmol
  • Second step Preparation of 2-bromo-N1-((1r,4r)-4-methylcyclohexyl)benzene-1,4-diamine
  • N-(3-bromo-4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)ethanesulfonamide 200mg, 0.5mmol
  • the compound N-(3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-) Methylcyclohexyl)amino)phenyl)ethanesulfonamide 180 mg, yield: 58%).
  • Step 5 N-(3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl) Preparation of amino)phenyl)ethanesulfonamide
  • N-(3-(6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methyl) Cyclohexyl)amino)phenyl)ethanesulfonamide 180 mg, 0.3 mmol was used as the starting material of the reaction, and the compound of N.sup. -b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)ethanesulfonamide (120 mg, yield: 91%).
  • Step 6 4-(5-(Ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[ Preparation of 2,3-b]pyridine-7-oxide
  • the second step preparation of 2-bromo-1-fluoro-4-(methanesulfonyl)benzene
  • the third step preparation of 2-bromo-1-(cyclohexanetrienoxy)-4-(methanesulfonyl)benzene
  • the solution was reacted at 85 ° C for 16 hours under a nitrogen atmosphere.
  • the reaction mixture was evaporated to dryness, and then purified,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
  • Step 5 Preparation of 4-(2-(cyclohexanetrienoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine
  • N-(cyclopropylmethyl)-4-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Aniline (200.0 mg, 0.57 mmol), dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL), followed by tris(dibenzylideneacetone) dipalladium (16 mg, 0.0171 mmol) , tripotassium phosphate (302 mg, 1.43 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (18.3 mg, 0.0627 mmol) The mixture was stirred with nitrogen for 5 minutes and stirred at 120 ° C for one hour.
  • N-(cyclopropylmethyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methylsulfonyl)aniline (21.0 mg, 0.056 Methyl acetate (2 mL) was added, and m-chloroperoxybenzoic acid (14 mg, 0.084 mmol) was added, and the mixture was stirred at room temperature for one hour and then quenched with sodium thiosulfate solution (5 mL). After the addition, dichloromethane (15 mL) was added, and then washed with water (20 mL ⁇ 2) and brine (20 mL) and dried over anhydrous sodium sulfate.
  • Second step Preparation of 2-(2-isobutoxy-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan
  • Step 2 4-(2-Fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine
  • the third step 4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
  • reaction mixture was diluted with ethyl acetate (20 mL) Wash (10 mL ⁇ 3), then wash with saturated brine (10 mL), EtOAc (EtOAc) /V), 4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.23 g, light) Yellow solid, yield 68%).
  • Trans-4-tert-butylcyclohexanol (0.10 g, 0.66 mmol) was dissolved in N,N-dimethylformamide (3 mL), then sodium hydride (60%, EtOAc, The reaction solution was stirred at room temperature for half an hour.
  • trans-4-methylcyclohexanol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((trans)-4-methylcyclohexyl)oxy).
  • -5-(Methanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide 0.035 g, white solid, yield 49%).
  • trans-4-ethylcyclohexanol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((trans)-4-ethylcyclohexyl)oxy).
  • -5-(Methanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide 0.023 g, white solid, yield 58%).
  • trans-4-isopropylcyclohexanol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((trans))-4-isopropylcyclohexyl.
  • Oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide 0.018 g, yield 44%).
  • the first step the preparation of 1,2-bis(3-bromo-4-fluorophenyl)disulfane.
  • the second step the preparation of 3-bromo-4-fluorobenzenethiol
  • 1,2-bis(3-bromo-4-fluorophenyl)disulfane 42 g, 101.9 mmol
  • methanol 300 mL
  • tetrahydrofuran 1 L
  • sodium hydroxide 10.3 g, 257.5
  • Step 7 2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 -yl)phenyl)sulfonyl)-2-methylpropionitrile
  • Step 8 2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonyl-2-methylpropionitrile
  • Step 9 4-(5-((2-Cyanopropan-2-yl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrole And [2,3-b]pyridine-7-oxide
  • Second step 2-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonyl acetonitrile
  • Second step 1-((4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 -yl)phenyl)sulfonyl)cyclopropane-1-carbonitrile
  • Example 23 Taking 1-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)cyclopropane-1-carbonitrile as the starting material, refer to the seventh step of Example 23 to obtain 1- ((4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonylcyclopropane-1-carbonitrile (0.05 g, white solid, yield 42%).
  • the third step 1-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonylcyclopropane-1-carbonitrile
  • reaction liquid is evaporated to dryness, and toluene and dilute hydrochloric acid are added to the reaction system, and the toluene phase is washed with dilute hydrochloric acid, water and saturated brine, and the organic phase is dried and evaporated to dryness, and the residue is subjected to distillation under reduced pressure to collect steam temperature 60-70 ° C.
  • 3-Bromo-4-fluorophenyl)(ethyl)sulfane (15 g, pale yellow oil, yield 64%).
  • the second step preparation of 2-bromo-4-(ethylsulfonyl)-1-fluorobenzene
  • Step 5 Preparation of 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
  • Step 6 4-(2-(Cyclohexanetrienoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 - Preparation of oxides
  • Example 26 Starting from cyclohexanol in place of cyclohexanol, the sixth step of Example 26 was carried out to obtain the compound 4-(2-(cyclobutyl)methoxy)-5-(ethylsulfonyl)phenyl)-6.
  • trans-4-tert-butylcyclohexanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, 4-(2-((trans)-4-(tert-butyl)cyclohexyl)oxo)- 5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation (0.040 g, white solid, yield 57%).
  • the trans-4-ethylcyclohexanol (0.077 g, 0.60 mmol) was dissolved in N,N-dimethylformamide (4 mL), then sodium hydride (60%, <RTIgt; After adding to the reaction solution, stirring at room temperature for half an hour, 4-(2-fluoro-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide (0.04 g, 0.12 mmol) of N,N-dimethylformamide (1 mL) was added dropwise to the reaction mixture.
  • reaction mixture was diluted with methylene chloride (20 mL), washed with NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide ( 0.008 g, white solid, yield 15%).
  • Second step 4-(2-(4-(aminomethyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Pyridine-7-oxide
  • Second step Preparation of (3-bromo-4-fluorophenyl)(2,2,2-trifluoroethyl)sulfane
  • the third step preparation of 2-bromo-1-fluoro-4-((2,2,2-trifluoroethyl)sulfonyl)benzene
  • Step 5 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1-toluene
  • Step 6 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine
  • Step 7 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine-7-oxide
  • Step 8 4-(2-(2,4-Difluorophenoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl) Preparation of -6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
  • reaction mixture was added ethyl acetate (50mL), then with saturated brine (50mL), dried over anhydrous sodium sulfate ,, and concentrated Purification by reverse phase preparative chromatography (C 18 column, mobile phase (acetonitrile / water To give 6-methyl-4-(2-((trans)-4-methylcyclohexyl)oxo)-5-((1,1,1-trifluoro-2-methylpropane-2) -yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (15.0 mg, yield 19%).

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Abstract

A pyrrolo-pyridines N-oxide derivative shown in formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and use of the compounds as a BRD4 inhibitor for treating related diseases, for example, cancers, inflammations, chronic liver diseases, diabetes, cardiovascular diseases, and AIDS.

Description

吡咯并吡啶类N-氧化衍生物及其制备方法和应用Pyrrolopyridine N-oxidation derivative and preparation method and application thereof 技术领域Technical field
本发明属于医药领域,涉及吡咯并吡啶类N-氧化衍生物、其制备方法和药物组合物在医药研究上的应用,本发明公开了其作为BRD4抑制剂在治疗癌症、炎症、慢性肝病、糖尿病、心血管疾病和AIDS等相关疾病的用途。The invention belongs to the field of medicine and relates to pyrrolopyridinium N-oxidized derivatives, a preparation method thereof and application of the pharmaceutical composition in medical research, and the invention discloses as a BRD4 inhibitor in treating cancer, inflammation, chronic liver disease and diabetes. The use of cardiovascular diseases and related diseases such as AIDS.
背景技术Background technique
肿瘤是严重危害人类生命的重大疾病之一,一半以上发生在发展中国家。我国恶性肿瘤发病率总体呈上升趋势,发病率以年均3%~5%的速度递增,预计到2020年,我国将有400万人发生癌症,300万人死于癌症,其主要原因是:老龄化、城镇化、工业化及生活习惯改变。在中国医院用药市场,抗肿瘤药物的销售规模近几年来一直稳步增长,2012年达到了664.2亿元,同比增长了13.07%,预计到2017年,抗肿瘤药物的市场规模将达到1055.7亿元,同比增长7.57%。Tumors are one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries. The incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3% to 5%. It is estimated that by 2020, 4 million people will develop cancer in China and 3 million will die of cancer. The main reasons are: Ageing, urbanization, industrialization and lifestyle changes. In China's hospital drug market, the sales scale of anti-cancer drugs has been growing steadily in recent years. In 2012, it reached 66.42 billion yuan, an increase of 13.07% year-on-year. It is expected that by 2017, the market size of anti-cancer drugs will reach 105.57 billion yuan. The year-on-year growth was 7.57%.
由于恶性肿瘤的无限制生长与浸润、转移,现今临床采用的三大常规治疗方法(手术、放疗和化疗)无法完全切除或彻底杀灭肿瘤细胞,因此常出现肿瘤转移或复发。肿瘤生物治疗是应用现代生物技术及其相关产品进行肿瘤防治的新疗法,因其安全、有效、不良反应低等特点,成为继手术、放疗、化疗之后肿瘤治疗的第四种模式,其通过调动宿主的天然防御机制或给予天然产生的靶向性很强的物质来获得抗肿瘤的效应。Due to the unrestricted growth and infiltration and metastasis of malignant tumors, the three conventional treatment methods (surgery, radiotherapy and chemotherapy) used in clinical practice cannot completely remove or completely kill tumor cells, so tumor metastasis or recurrence often occurs. Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy. The natural defense mechanism of the host or the naturally occurring highly targeted substance is obtained to obtain an anti-tumor effect.
溴结构蛋白4(BRD4)是溴结构域和超末端结构(bromodomain and extraterminal domain,BET)家族成员,BRD4通过招募不同的转录调节因子,如Mediator、正性转录延伸因子b(positive transcription elongation factor b,P-TEFb)来调节靶基因的表达。作为一种在哺乳动物中广泛表达的染色质“适配器,reader”,可以在整个有丝分裂过程中识别乙酰化的蛋白结合到染色体上,募集不同的染色质修饰蛋白,广泛调控基因的表达,从而在调控细胞周期进程、转录、炎症等方面发挥重要作用。最近的研究表明BRD4的表达水平失调或功能紊乱与睾丸核蛋白中线癌(midline carcinoma with rearrangement of the nuclear protein intestis gene,NMC)、黑色素瘤、急性髓系白血病、结肠癌、乳腺癌等的发生有关。BRD4shRNA或BET抑制剂可以诱导上述肿瘤发生细胞周期阻滞、凋亡及细胞分化,显示出强大的抗肿瘤活性。这些发现表明,BET蛋白有望成为上述肿瘤甚至其他肿瘤新的治疗靶点。另外,通过工具化合物JQ1等研究发现,BRD4的抑制剂在病毒感染,糖尿病,代谢性疾病,肝脏疾病和老年痴呆症等多种疾病均可能有较广泛的运用。Bromostructured protein 4 (BRD4) is a member of the bromodomain and extraterminal domain (BET) family, and BRD4 recruits different transcriptional regulators such as Mediator, positive transcription elongation factor b (positive transcription elongation factor b) , P-TEFb) to regulate the expression of the target gene. As a chromatin "reader" widely expressed in mammals, it can recognize acetylated proteins to bind to chromosomes throughout mitosis, recruit different chromatin-modifying proteins, and widely regulate gene expression. It plays an important role in regulating cell cycle progression, transcription, and inflammation. Recent studies have shown that dysregulation or dysfunction of BRD4 is associated with the occurrence of midline carcinoma with rearrangement of the nuclear protein intestis gene (NMC), melanoma, acute myeloid leukemia, colon cancer, breast cancer, etc. . BRD4 shRNA or BET inhibitor can induce cell cycle arrest, apoptosis and cell differentiation of the above tumors, and exhibits strong antitumor activity. These findings suggest that BET protein is expected to be a new therapeutic target for these and even other tumors. In addition, studies by the tool compound JQ1 and the like have found that BRD4 inhibitors may be widely used in various diseases such as viral infection, diabetes, metabolic diseases, liver diseases and Alzheimer's disease.
BRD4抑制剂作为药物在医药行业具有良好的应用前景,目前还没有上市的 药物,为了达到更好的治疗效果的目的和满足市场需求,我们希望能开发出新一代的高效低毒的选择性BRD4抑制剂。BRD4 inhibitors have good application prospects in the pharmaceutical industry as pharmaceuticals. Currently, there are no listed drugs. In order to achieve better therapeutic effects and meet market demand, we hope to develop a new generation of highly efficient and low toxicity selective BRD4. Inhibitor.
发明内容Summary of the invention
本发明的目的在于提供一种通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐,其中通式(I)所示的化合物结构如下:The object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture form, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) has the following structure:
Figure PCTCN2018073989-appb-000001
Figure PCTCN2018073989-appb-000001
其中:among them:
X、Y各自独立地选自键、N、O、-NR 5-、-(CR 6R 7) x-和-(CR 6R 7) xN(R 5) y-; X, Y are each independently selected from the group consisting of a bond, N, O, -NR 5 -, -(CR 6 R 7 ) x -, and -(CR 6 R 7 ) x N(R 5 ) y -;
Z选自-NR 5-、O和-O(CR 6R 7) x-; Z is selected from -NR 5 -, O and -O(CR 6 R 7 ) x -;
环A选自环烷基、杂环基、芳基和杂芳基;Ring A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
R 1选自烷基、环烷基和烯基;其中所述的烷基、烯基和环烷基任选进一步被选自烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、环烷基、杂环基、芳基和杂芳基的中的一个或多个取代基所取代; R 1 is selected from the group consisting of alkyl, cycloalkyl and alkenyl; wherein said alkyl, alkenyl and cycloalkyl are optionally further selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy Substituted by one or more substituents of a group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
R 2选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、烯烃、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10;其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an olefin, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C( O) R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from alkyl, haloalkanes Base, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O) R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S (O) substituted with one or more substituents in m R 10 ;
R 3选自不存在、氢原子、烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10;其中所述的烷基、卤代烷基、烯烃、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; R 3 is selected from the group consisting of a non-existent hydrogen atom, an alkyl group, a halogenated alkyl group, an alkene group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a hetero group. Aryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl, haloalkyl, olefin, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected From alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 And one or more substituents in -NR 9 S(O) m R 10 are substituted;
或者,R 2和R 3连接形成一个杂环基或杂芳基;其中所述的杂环基和杂芳基任选进一步被选自烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; Alternatively, R 2 and R 3 are bonded to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl are optionally further selected from the group consisting of alkyl, haloalkyl, alkene, alkoxy, haloalkoxy , halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S (O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m One or more substitutions in R 10 Substituted by
再或者,R 2、R 3各自独立地与X基团上的R 6、R 7或R 5连接形成一个杂环基或杂芳基;其中所述的杂环基和杂芳基任选进一步被选自烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; Further, R 2 and R 3 are each independently bonded to R 6 , R 7 or R 5 on the X group to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl group are optionally further Selected from alkyl, haloalkyl, olefin, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 And one or more substituents in -NR 9 S(O) m R 10 are substituted;
R 4独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-(CH 2) tNR 9R 10、-(CH 2) tC(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10;其中所述的烷基、环烷基、杂环基、芳基、杂芳基任选进一步被选自烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、羟烷基、卤素、卤代烷基、烷基取代杂环基、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; R 4 is independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, Heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -(CH 2 ) t NR 9 R 10 , -(CH 2 ) t C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Further optionally, it is selected from the group consisting of alkyl, haloalkyl, olefin, alkoxy, haloalkoxy, hydroxyalkyl, halogen, haloalkyl, alkyl substituted heterocyclic, amino, nitro, hydroxy, cyano, cyclo Alkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 ,- Substituting one or more substituents of C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ;
R 5选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基; R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
R 6和R 7各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group. , aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ;
或者,R 6和R 7可以形成环烷基或杂环基,该环烷基或杂环基任选进一步被选自烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; Alternatively, R 6 and R 7 may form a cycloalkyl or heterocyclic group, which is optionally further selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halogen , amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m One or more substituents in R 10 Replace
R 8选自氢原子、烷基、卤代烷基、烯基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基;其中所述的烷基、卤代烷基、烯基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、卤代烷基、氨基、硝基、氰基、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; R 8 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, Haloalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halo, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy Base, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R Substituting one or more substituents of 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ;
R 9和R 10相同或不同,且各自独立地选自氢原子、烷基、羟基、氨基、环烷 基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基、中的一个或多个取代基所取代; R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group And a heterocyclic group, an aryl group and a heteroaryl group are further selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group. And substituted with one or more substituents in the heteroaryl;
m为0、1或2的整数;m is an integer of 0, 1, or 2;
n为0、1、2、3、4或5的整数;n is an integer of 0, 1, 2, 3, 4 or 5;
t为0、1、2、3、4或5的整数;t is an integer of 0, 1, 2, 3, 4 or 5;
x为0、1、2、3或4的整数;且x is an integer of 0, 1, 2, 3 or 4;
y为0或1的整数。y is an integer of 0 or 1.
在本发明的一个优选实施例方案中,所述的通式(I)所示的化合物,其为通式(II)所示的化合物:In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (II):
Figure PCTCN2018073989-appb-000002
Figure PCTCN2018073989-appb-000002
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中:among them:
B选自CH和N;B is selected from CH and N;
R 1~R 4、Z、X、Y和n如通式(I)中所定义。 R 1 to R 4 , Z, X, Y and n are as defined in the formula (I).
在本发明的一个优选实施例方案中,所述的通式(I)所示的化合物,其为通式(III)所示的化合物:In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (III):
Figure PCTCN2018073989-appb-000003
Figure PCTCN2018073989-appb-000003
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中:among them:
B选自CH和N;B is selected from CH and N;
R 1、R 2、R 4、Z、X和n如通式(I)中所定义。 R 1 , R 2 , R 4 , Z, X and n are as defined in the formula (I).
在本发明的一个优选实施例方案中,所述的通式(I)所示的化合物,其为通 式(IV)所示的化合物:In a preferred embodiment of the invention, the compound of the formula (I) is a compound of the formula (IV):
Figure PCTCN2018073989-appb-000004
Figure PCTCN2018073989-appb-000004
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中:among them:
Z选自NH和O;Z is selected from NH and O;
B选自CH和N;B is selected from CH and N;
环C选自环烷基、杂环基、芳基和杂芳基,其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;且Ring C is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halogen, amino, Substituted by one or more substituents of a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
z为0、1、2或3的整数;z is an integer of 0, 1, 2 or 3;
R 1、R 2、R 4、X和n如通式(I)中所定义。 R 1 , R 2 , R 4 , X and n are as defined in the formula (I).
在本发明的一个优选实施例方案中,所述的通式(IV)所示的化合物,其为通式(VA)或(VB)所示的化合物:In a preferred embodiment of the present invention, the compound represented by the formula (IV) is a compound represented by the formula (VA) or (VB):
Figure PCTCN2018073989-appb-000005
Figure PCTCN2018073989-appb-000005
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中:among them:
Z选自NH和O;Z is selected from NH and O;
X选自键、NH和-CR 6R 7-; X is selected from the group consisting of a bond, NH and -CR 6 R 7 -;
R 4选自氢原子、卤素、羟基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6羟烷基、C 3-6环烷基、-(CH 2) tNR 9R 10和-(CH 2) tC(O)NR 9R 10R 4 is selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 3-6 cycloalkyl group, -(CH 2 ) t NR 9 R 10 and -(CH 2 ) t C(O)NR 9 R 10 ;
R 2选自C 1-6烷基、卤代C 1-6烷基、-NR 9R 10、C 3-6环烷基或5-6元杂芳基;其中所述的C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基和5-6元杂芳基任选进一步被选自C 1-6烷基、卤代C 1-6烷基、卤素、氨基、氰基和羟基中的一个或多个取代基所 取代; R 2 is selected from C 1-6 alkyl, halo C 1-6 alkyl, -NR 9 R 10 , C 3-6 cycloalkyl or 5-6 membered heteroaryl; wherein said C 1-6 The alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are further optionally selected from C 1-6 alkyl groups, halogenated C 1-6 alkyl groups, halogen Substituting one or more substituents of an amino group, a cyano group and a hydroxyl group;
R 6、R 7相同或不同,各自独立地选自氢原子和C 1-3烷基; R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group;
R 9、R 10相同或不同,各自独立地选自氢原子和C 1-3烷基; R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group;
n、t如通式(I)中所定义。n, t is as defined in the general formula (I).
在本发明的一个优选实施例方案中,所述的通式(IV)所示的化合物,其为通式(VIA)或(VIB)所示的化合物:In a preferred embodiment of the invention, the compound of the formula (IV) is a compound of the formula (VIA) or (VIB):
Figure PCTCN2018073989-appb-000006
Figure PCTCN2018073989-appb-000006
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中:among them:
Z选自NH和O;Z is selected from NH and O;
X选自键、NH和-CR 6R 7-; X is selected from the group consisting of a bond, NH and -CR 6 R 7 -;
R C独立地选自氢原子、卤素、羟基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6羟烷基、C 3-6环烷基、-(CH 2) tNR 9R 10或-(CH 2) tC(O)NR 9R 10R C is independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 3-6 cycloalkyl group, a ( CH 2 ) t NR 9 R 10 or -(CH 2 ) t C(O)NR 9 R 10 ;
R 2选自C 1-6烷基、卤代C 1-6烷基、-NR 9R 10、C 3-6环烷基和5-6元杂芳基;其中所述的C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基和5-6元杂芳基任选进一步被选自C 1-6烷基、卤代C 1-6烷基、卤素、氨基、氰基和羟基中的一个或多个取代基所取代; R 2 is selected from C 1-6 alkyl, halo C 1-6 alkyl, -NR 9 R 10 , C 3-6 cycloalkyl and 5-6 membered heteroaryl; wherein said C 1-6 The alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are further optionally selected from C 1-6 alkyl groups, halogenated C 1-6 alkyl groups, halogen Substituting one or more substituents of an amino group, a cyano group and a hydroxyl group;
R 6、R 7相同或不同,各自独立地选自氢原子和C 1-3烷基; R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group;
R 9、R 10相同或不同,各自独立地选自氢原子和C 1-3烷基; R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group;
t如权利要求1中所定义。t as defined in claim 1.
在本发明的一个优选实施例方案中,所述的各通式所示的化合物,其中R 1选自C 1-8烷基、C 2-8烯基和C 3-8环烷基;优选C 1-6烷基、C 2-6烯基或C 3-6环烷基;更优选C 1-3烷基、C 2-3烯基或C 3-6环烷基;最优选甲基。 In a preferred embodiment of the invention, the compound of the above formula, wherein R 1 is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl and C 3-8 cycloalkyl; C 1-6 alkyl, C 2-6 alkenyl or C 3-6 cycloalkyl; more preferably C 1-3 alkyl, C 2-3 alkenyl or C 3-6 cycloalkyl; most preferably methyl .
在本发明的一个优选实施例方案中,所述的各通式所示的化合物,其中R 2选自C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基和5-6元杂芳基,其中所述的C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基和5-6元杂芳基任选进一步被选自C 1-6烷基、卤代C 1-6烷基、卤素、氨基、氰基和羟基中的一个或多个取代基所取代;优选C 1-6烷基、卤代C 1-6烷基或C 3-6环烷基;更优选C 1-3烷基、卤代C 1-3烷基或C 3-6环烷基,最优选甲基、乙基、异丙基、环丙基、环丁基、
Figure PCTCN2018073989-appb-000007
In a preferred embodiment of the invention, the compound of the formula, wherein R 2 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, and a -6 membered heteroaryl group, wherein said C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are optionally further selected from C 1 Substituted by one or more substituents of -6 alkyl, halo C 1-6 alkyl, halogen, amino, cyano and hydroxy; preferably C 1-6 alkyl, halo C 1-6 alkyl or C 3-6 cycloalkyl; more preferably C 1-3 alkyl, halo C 1-3 alkyl or C 3-6 cycloalkyl, most preferably methyl, ethyl, isopropyl, cyclopropyl, Cyclobutyl,
Figure PCTCN2018073989-appb-000007
在本发明的一个优选实施例方案中,所示的式(I)化合物选自如下化合物:In a preferred embodiment of the invention, the compound of formula (I) is selected from the group consisting of:
Figure PCTCN2018073989-appb-000008
Figure PCTCN2018073989-appb-000008
Figure PCTCN2018073989-appb-000009
Figure PCTCN2018073989-appb-000009
Figure PCTCN2018073989-appb-000010
Figure PCTCN2018073989-appb-000010
Figure PCTCN2018073989-appb-000011
Figure PCTCN2018073989-appb-000011
Figure PCTCN2018073989-appb-000012
Figure PCTCN2018073989-appb-000012
Figure PCTCN2018073989-appb-000013
Figure PCTCN2018073989-appb-000013
Figure PCTCN2018073989-appb-000014
Figure PCTCN2018073989-appb-000014
Figure PCTCN2018073989-appb-000015
Figure PCTCN2018073989-appb-000015
Figure PCTCN2018073989-appb-000016
Figure PCTCN2018073989-appb-000016
Figure PCTCN2018073989-appb-000017
Figure PCTCN2018073989-appb-000017
Figure PCTCN2018073989-appb-000018
Figure PCTCN2018073989-appb-000018
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用的盐。Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
在本发明的一个优选实施例方案中,一种所述通式(I)所示的化合物的中间体,其为通式(V)化合物、通式(VAA)化合物或通式(VBB)化合物:In a preferred embodiment of the present invention, an intermediate of the compound of the formula (I), which is a compound of the formula (V), a compound of the formula (VAA) or a compound of the formula (VBB) :
Figure PCTCN2018073989-appb-000019
Figure PCTCN2018073989-appb-000019
或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物 形式,或其可药用盐,Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
其中:among them:
R 1~R 4、环A、Z、X、Y和n如通式(I)中所定义。 R 1 to R 4 , ring A, Z, X, Y and n are as defined in the formula (I).
在本发明的一个优选实施例方案中,一种通式(I)所示的化合物的制备方法,包括如下步骤:In a preferred embodiment of the present invention, a method for preparing a compound of the formula (I) comprises the following steps:
Figure PCTCN2018073989-appb-000020
Figure PCTCN2018073989-appb-000020
通式(V)化合物经氧化剂氧化后得到通式(I)化合物;氧化剂优选间氯过氧苯甲酸;The compound of the formula (V) is oxidized by an oxidizing agent to give a compound of the formula (I); the oxidizing agent is preferably m-chloroperoxybenzoic acid;
其中:among them:
R 1~R 4、环A、Z、X、Y和n如通式(I)中所定义; R 1 to R 4 , ring A, Z, X, Y and n are as defined in the formula (I);
在本发明的一个优选实施例方案中,一种通式(VA)所示的化合物的制备方法,包括如下步骤:In a preferred embodiment of the present invention, a method for preparing a compound represented by the formula (VA) comprises the following steps:
Figure PCTCN2018073989-appb-000021
Figure PCTCN2018073989-appb-000021
通式(VAA)化合物经氧化剂氧化后得到通式(VA)化合物;氧化剂优选间氯过氧苯甲酸;The compound of the formula (VAA) is oxidized by an oxidizing agent to give a compound of the formula (VA); the oxidizing agent is preferably m-chloroperoxybenzoic acid;
其中:among them:
R 2、R 4、Z、X和n如通式(VA)中所定义; R 2 , R 4 , Z, X and n are as defined in the formula (VA);
在本发明的一个优选实施例方案中,一种通式(VB)所示的化合物的制备方法,包括如下步骤:In a preferred embodiment of the present invention, a method for preparing a compound represented by the formula (VB) comprises the following steps:
Figure PCTCN2018073989-appb-000022
Figure PCTCN2018073989-appb-000022
通式(VBB)化合物经氧化剂氧化后得到通式(VB)化合物;氧化剂优选间氯过氧苯甲酸;The compound of the formula (VBB) is oxidized by an oxidizing agent to give a compound of the formula (VB); the oxidizing agent is preferably m-chloroperoxybenzoic acid;
其中:among them:
R 2、R 4、Z、X和n如通式(VB)中所定义; R 2 , R 4 , Z, X and n are as defined in the formula (VB);
本发明的另一方面涉及一种药物组合物,其含有治疗有效剂量的各通式所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。本发明还涉及一种制备上述药物组合物的方法,其包括将各通式所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其可药用的盐与药学上可接受的载体、稀释剂或赋形剂相混合。Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The present invention also relates to a process for the preparation of the above pharmaceutical composition which comprises the compounds of the formulas or their tautomers, meso, racemates, enantiomers, non-pairs The conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is admixed with a pharmaceutically acceptable carrier, diluent or excipient.
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物在制备用于预防和/或治疗预防作为BRD4抑制剂在治疗癌症、炎症、AIDS的药物中的用途。。The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the preparation of a medicament for the prophylaxis and/or treatment of a medicament for the treatment of cancer, inflammation, AIDS as a BRD4 inhibitor. .
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物在制备BRD4抑制剂药物中的应用。The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, in the manufacture of a BRD4 inhibitor drug.
本发明进一步涉及通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物在制备治疗癌症、炎症、慢性肝病、糖尿病、心血管疾病和AIDS的药物中的应用。The invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the manufacture of a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS.
本发明还涉及一种治疗预防和/或治疗预防BRD4介导的病理学特征的疾病的方法,其包括向患者施用治疗有效剂量的通式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,或包含其的药物组合物The present invention also relates to a method of treating a disease preventing and/or treating a BRD4-mediated pathological feature comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof. , a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same
本发明另一方面涉及一种治疗癌症的方法,该方法包括向患者施用治疗有效剂量的本发明的通式(I)所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐。该方法显示出突出的疗效和较少的副作用。Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. This method shows outstanding efficacy and fewer side effects.
本发明另一方面涉及一种治疗炎症的方法,该方法包括向患者施用治疗有效剂量的本发明的通式(I)所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐。该方法显示出突出的疗效和较少的副作用。Another aspect of the invention relates to a method of treating inflammation comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof. This method shows outstanding efficacy and fewer side effects.
本发明另一方面涉及一种治疗慢性肝病的方法,该方法包括向患者施用治疗有效剂量的本发明的通式(I)所述的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐。该方法显示出突出的疗效和较少的副作用。Another aspect of the invention relates to a method of treating chronic liver disease, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, or an external Racemates, enantiomers, diastereomers or mixtures thereof, or a pharmaceutically acceptable salt thereof. This method shows outstanding efficacy and fewer side effects.
本发明所述的癌症可以选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、肝癌、实体瘤、神经胶质瘤、神经胶母细胞瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌;所述的慢性肝病选自:原发性硬化(PBC)、脑脏性黄瘤症(CTX)、原发性硬化性胆囊炎(PSC)、药物导致的胆汁郁积、妊娠肝内胆汁淤积症、肠外吸收相关胆汁郁积(PNAC)、细菌过度生长或脓血症胆汁郁积、自身免疫肝炎、慢性病毒性肝炎、酒精性肝病、非酒精性脂肪肝疾病(NAFLD)、非酒精性脂肪性肝炎(NASH)、肝移植相关移植物抗宿主病、活供体肝移植再生、先天性肝纤维化、胆总管结石、肉芽性肝病、肝内或外恶性肿瘤、Sjogren综合征、结节病、Wilson's疾病、Gaucher's疾病、血色病或α 1一抗膜蛋白酶缺乏症。 The cancer of the present invention may be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, glioblastoma, leukemia, lymph. Tumor, myeloma and non-small cell lung cancer; said chronic liver disease is selected from the group consisting of: primary sclerosis (PBC), cerebral xanthoma (CTX), primary sclerosing cholecystitis (PSC), drug-induced Cholestasis, intrahepatic cholestasis of pregnancy, parenteral absorption-related cholestasis (PNAC), bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD) ), nonalcoholic steatohepatitis (NASH), liver graft-related graft-versus-host disease, live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren Syndrome, sarcoidosis, Wilson's disease, Gaucher's disease, hemochromatosis or alpha 1 anti-membrane protease deficiency.
发明的详细说明Detailed description of the invention
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。Terms used in the specification and claims have the following meanings unless stated to the contrary.
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至8个碳原子的烷基,更优选1至6个碳原子的烷基,最更优选1至3个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基,及其各种支链异构体等。烷基可以是取代的或非取代的,当被取代时,取代基可以在任何可使用的连接点上被取代,所述取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms. The alkyl group is most preferably an alkyl group of 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-B Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-B Hexyl group, 2,2- Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic An oxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
术语“亚烷基”是指烷基的一个氢原子进一步被取代,例如:“亚甲基”指-CH 2-、“亚乙基”指-(CH 2) 2-、“亚丙基”指-(CH 2) 3-、“亚丁基”指-(CH 2) 4-等。 The term "alkylene" means that one hydrogen atom of the alkyl group is further substituted, for example, "methylene" refers to -CH 2 -, "ethylene" refers to -(CH 2 ) 2 -, "propylene" Refers to -(CH 2 ) 3 -, "butylene" means -(CH 2 ) 4 - and the like.
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基,例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、 氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。The term "alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio group.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等;多环环烷基包括螺环、稠环和桥环的环烷基,优选环丙基、环丁基、环己基、环戊基和环庚基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms. One carbon atom. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上,其中与母体结构连接在一起的环为环烷基,非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1~4个是杂原子;更优选包含3至8个环原子;最优选包含3至8个环原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等,优选四氢呋喃基和吡喃基。多环杂环基包括螺环、稠环和桥环的杂环基。 The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O). A hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably comprises from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; more preferably from 3 to 8 ring atoms; most preferably from 3 to 8 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine. The base, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl and the like are preferably tetrahydrofuranyl and pyranyl. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
术语“稠杂环基”指5至20元,系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子系统,其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为3元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括: The term "fused heterocyclyl" refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic ring, more preferably a 3 member/5 member or a 5 member/6 membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:
Figure PCTCN2018073989-appb-000023
Figure PCTCN2018073989-appb-000023
杂环基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团,优选为6至10元,例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环,其非限制性实例包括:
Figure PCTCN2018073989-appb-000024
The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. More preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
Figure PCTCN2018073989-appb-000024
芳基可以是取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle An alkylthio group, a carboxyl group or a carboxylate group.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。杂芳基优选为5至10元,更优选为5元或6元,例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等,优选为咪唑基、吡唑基或嘧啶基、噻唑基;更有选嘧啶基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,其非限制性实例包括:The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, A pyrimidinyl group, a thiadiazole, a pyrazinyl group or the like is preferably an imidazolyl group, a pyrazolyl group or a pyrimidinyl group, or a thiazolyl group; and a pyrimidyl group is more preferred. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2018073989-appb-000025
Figure PCTCN2018073989-appb-000025
杂芳基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基的定义如上所述。烷氧基的非限制性实例包括:甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯 基。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.
术语“卤代烷基”指被一个或多个卤素取代的烷基,其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein alkyl is as defined above.
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基,其中烷氧基如上所定义。The term "haloalkoxy" refers to an alkoxy group substituted by one or more halogens, wherein alkoxy is as defined above.
术语“羟烷基”指被羟基取代的烷基,其中烷基如上所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
术语“羟基”指-OH基团。The term "hydroxy" refers to an -OH group.
术语“卤素”指氟、氯、溴或碘。The term "halogen" means fluoro, chloro, bromo or iodo.
术语“氨基”指-NH 2The term "amino" means -NH 2.
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2The term "nitro" refers to -NO 2 .
术语“氧代基”指=O。The term "oxo" refers to =0.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基),其中烷基如上所定义。The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl is as defined above.
“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义,即表示X可以是A、B、C中的任意一种或几种。"X is selected from A, B, or C", "X is selected from A, B, and C", "X is A, B, or C", and "X is A, B, and C" and the like are expressed in the same language. Meaning, that is, X can be any one or several of A, B, and C.
本发明所述的氢原子均可被其同位素氘所取代,本发明涉及的实施例化合物中的任一氢原子也均可被氘原子取代。The hydrogen atom of the present invention may be substituted by its isotope ruthenium, and any of the hydrogen atoms in the examples of the present invention may also be substituted by a ruthenium atom.
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生的场合。例如,“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .
“取代的”指基团中的一个或多个氢原子,优选为最多5个,更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻,取代基仅处在它们的可能的化学位置,本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如,具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物,以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药,利于活性成分的吸收进而发挥生物活性。"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
“可药用盐”是指本发明化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性。"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
具体实施方式detailed description
以下结合实施例进一步描述本发明,但这些实施例并非限制着本发明的范围。The invention is further described in the following examples, which are not intended to limit the scope of the invention.
实施例Example
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD),内标为四甲基硅烷(TMS),化学位移是以10 -6(ppm)作为单位给出。 The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four. Methylsilane (TMS), chemical shifts are given in units of 10 -6 (ppm).
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo,型号:Finnigan LCQ advantage MAX)。The measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
HPLC的测定使用安捷伦1200DAD高压液相色谱仪(Sunfire C18 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
激酶平均抑制率及IC 50值的测定用NovoStar酶标仪(德国BMG公司)。 The average value of 50 measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.2mm,薄层层析分离纯化产物采用的规格是0.4mm~0.5mm硅胶板。The thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. The specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm~0.2mm. The specification for separation and purification of thin layer chromatography is 0.4mm. ~0.5mm silica gel plate.
柱层析一般使用烟台黄海200~300目硅胶为载体。Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成,或可购买自ABCR GmbH&Co.KG,Acros Organnics,Aldrich Chemical Company,韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Dari Companies such as chemicals.
实施例中如无特殊说明,反应均在氩气氛或氮气氛下进行。In the examples, unless otherwise specified, the reactions were all carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
氢化反应通常抽真空,充入氢气,反复操作3次。The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
微波反应使用CEM Discover-S 908860型微波反应器。The microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
实施例中如无特殊说明,反应中的溶液是指水溶液。In the examples, the solution in the reaction means an aqueous solution unless otherwise specified.
实施例中如无特殊说明,反应的温度为室温。In the examples, the temperature of the reaction was room temperature unless otherwise specified.
室温为最适宜的反应温度,温度范围是20℃~30℃。Room temperature is the most suitable reaction temperature, and the temperature range is from 20 ° C to 30 ° C.
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂的体系有:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:石油醚和乙酸乙酯体系,D:丙酮,溶剂的体积比根据化合物的极性不同而进行调节。The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂的体系包括:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:正己烷、乙酸乙酯和二氯甲烷体系,D:石油醚和乙酸乙酯体系,E:乙酸乙酯,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺和酸性或碱性试剂等进行调节。The system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, acetic acid Ethyl ester and dichloromethane system, D: petroleum ether and ethyl acetate system, E: ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acid or alkali may be added. The reagents and the like are adjusted.
实施例1Example 1
4-(2-(2,4-二氟苯氧基)-5-(乙基磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide
Figure PCTCN2018073989-appb-000026
Figure PCTCN2018073989-appb-000026
第一步:4-氯-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备First step: Preparation of 4-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000027
Figure PCTCN2018073989-appb-000027
在室温下,将间氯过氧苯甲酸(14g,69mmol,w/w 85%)分批加入4-氯-7-氮杂吲哚(7g,46mmol)的四氢呋喃(150mL)溶液中。反应6小时后,大量固体生成,过滤收集固体,得到4-氯-1H-吡咯并[2,3-b]吡啶-7-氧化物(5.2g,产率67%)。m-Chloroperoxybenzoic acid (14 g, 69 mmol, w/w 85%) was added portionwise to a solution of 4-chloro-7- azaindole (7 g, 46 mmol) in tetrahydrofurane (150 mL). After 6 hours of reaction, a large amount of solid was formed, and solid was collected by filtration to give 4-chloro-1H-pyrrolo[2,3-b]pyridine-7-oxide (5.2 g, yield 67%).
1H NMR(400MHz,DMSO-d 6):δ12.85(br,1H),8.15(d,J=6.6Hz,1H),7.57(d,J=3.3Hz,1H),7.21(d,J=6.6Hz,1H),6.60(d,J=3.3Hz,1H). 1 H NMR (400MHz, DMSO- d 6): δ12.85 (br, 1H), 8.15 (d, J = 6.6Hz, 1H), 7.57 (d, J = 3.3Hz, 1H), 7.21 (d, J =6.6 Hz, 1H), 6.60 (d, J = 3.3 Hz, 1H).
第二步:(6-溴-4-氯-1H-吡咯并[2,3-b]吡啶-1-基)(苯基)甲酮的制备Second step: Preparation of (6-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone
Figure PCTCN2018073989-appb-000028
Figure PCTCN2018073989-appb-000028
将苯甲酰溴(14.3g,77mmol)和二(三甲基甲硅烷基)胺(5g,31mmol)平行同时缓慢滴加到4-氯-1H-吡咯并[2,3-b]吡啶-7-氧化物(5.2g,31mmol)的四氢呋喃(75mL)溶液中,时间大约30分钟,温度保持在20~30℃。滴加完毕后,室温反应3小时。反应液用碳酸氢钠饱和溶液中和,乙酸乙酯(25mL×2)萃取,将有机相合并,用Na 2SO 4干燥后浓缩。粗品经柱分离(乙酸乙酯:石油醚=1:10,V/V)得到(6-溴-4-氯-1H-吡咯并[2,3-b]吡啶-1-基)(苯基)甲酮(2.5g,产率24%)。 Benzoyl bromide (14.3 g, 77 mmol) and bis(trimethylsilyl)amine (5 g, 31 mmol) were added dropwise in parallel while slowly adding dropwise to 4-chloro-1H-pyrrolo[2,3-b]pyridine- In a solution of 7-oxide (5.2 g, 31 mmol) in tetrahydrofuran (75 mL) for about 30 minutes, the temperature was maintained at 20 to 30 °C. After the completion of the dropwise addition, the reaction was carried out for 3 hours at room temperature. The reaction was washed with saturated sodium bicarbonate solution and ethyl acetate (25mL × 2) and extracted, the organic phases are combined, dried Na 2 SO 4 dried and concentrated. The crude product was separated by column (ethyl acetate: petroleum ether = 1:10, V/V) to afford (6-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl) ) ketone (2.5 g, yield 24%).
1H NMR(400MHz,CDCl 3):δ7.81–7.74(m,3H),7.69–7.63(m,1H),7.51(m,2H),7.41(s,1H),6.74(d,J=4.0Hz,1H). 1 H NMR (400MHz, CDCl 3 ): δ7.81-7.74 (m, 3H), 7.69-7.63 (m, 1H), 7.51 (m, 2H), 7.41 (s, 1H), 6.74 (d, J = 4.0Hz, 1H).
第三步:4-氯-6-甲基-1H-吡咯并[2,3-b]吡啶的制备The third step: preparation of 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000029
Figure PCTCN2018073989-appb-000029
将二甲基锌的甲苯(4mL,4mmol,1M)溶液在氮气保护下缓慢滴加到(6-溴-4-氯-1H-吡咯并[2,3-b]吡啶-1-基)(苯基)甲酮(1.7g,5mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(365mg,0.5mmol)的四氢呋喃(20mL)溶液中。反应液在氮气保护下,70℃反应16小时。反应液冷却后用饱和碳酸氢钠溶液(10mL)淬灭后用乙酸乙酯(25mL×2)萃取,将有机相合并,干燥后浓缩得到粗品。粗品经柱分离(乙酸乙酯:石油醚=1:1,V/V)得到4-氯-6-甲基-1H-吡咯并[2,3-b]吡啶(290mg,产率35%)。A solution of dimethylzinc in toluene (4 mL, 4 mmol, 1 M) was slowly added dropwise to (6-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl) under nitrogen. Phenyl) ketone (1.7 g, 5 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (365 mg, 0.5 mmol) in tetrahydrofuran (20 mL). The reaction solution was reacted at 70 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled with EtOAc EtOAc m. The crude product was separated by column (ethyl acetate: petroleum ether = 1:1, V/V) to give 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine (290 mg, yield 35%) .
1H NMR(400MHz,CDCl 3):δ10.25(br,1H),7.30(d,J=3.5Hz,1H),7.04(s,1H),6.58(d,J=3.5Hz,1H),2.65(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ10.25 (br, 1H), 7.30 (d, J = 3.5Hz, 1H), 7.04 (s, 1H), 6.58 (d, J = 3.5Hz, 1H), 2.65 (s, 3H).
MS m/z(ESI):167.0[M+H] + MS m/z (ESI): 167.0 [M+H] +
第四步:2-溴-1-(2,4-二氟苯氧基)-4-硝基苯的制备The fourth step: preparation of 2-bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene
Figure PCTCN2018073989-appb-000030
Figure PCTCN2018073989-appb-000030
将2-溴-1-氟-4-硝基苯(14g,107.7mmol)、2,4-二氟苯酚(19.6g,89.7mmol)溶于DMSO(100mL)中,在室温下加入碳酸铯(35g,17.7mmol),然后在110℃搅拌2小时。反应液中加入水(150mL),然后用乙酸乙酯(200mL)萃取,有机相用饱和食盐水洗(100mL,无水硫酸钠干燥,然后浓缩得2-溴-1-(2,4-二氟苯氧基)-4-硝基苯,粗品直接用于下一步反应。2-Bromo-1-fluoro-4-nitrobenzene (14 g, 107.7 mmol), 2,4-difluorophenol (19.6 g, 89.7 mmol) was dissolved in DMSO (100 mL) and cesium carbonate was added at room temperature ( 35 g, 17.7 mmol), then stirred at 110 ° C for 2 hours. Water (150 mL) was added to the reaction mixture, and the mixture was evaporated. EtOAc (EtOAc) Phenoxy)-4-nitrobenzene, the crude product was used directly in the next reaction.
第五步:3-溴-4-(2,4-二氟苯氧基)苯胺的制备Step 5: Preparation of 3-bromo-4-(2,4-difluorophenoxy)aniline
Figure PCTCN2018073989-appb-000031
Figure PCTCN2018073989-appb-000031
将2-溴-1-(2,4-二氟苯氧基)-4-硝基苯(29g,88.4mmol)溶于乙醇(160mL)、四氢呋喃(160mL)、水(56mL),加入铁粉(24.7g,442mmol)、氯化铵(9.45g,176.8mmol)。升温至100℃,搅拌1.5小时,经硅藻土过滤,滤液脱除溶剂,加入二氯甲烷(250mL)萃取,将有机相干燥,过滤后的滤液减压脱除二氯甲烷得到3-溴-4-苯氧基苯胺(22.0g,产率83%)。2-Bromo-1-(2,4-difluorophenoxy)-4-nitrobenzene (29 g, 88.4 mmol) was dissolved in ethanol (160 mL), tetrahydrofuran (160 mL), water (56 mL). (24.7 g, 442 mmol), ammonium chloride (9.45 g, 176.8 mmol). The mixture was heated to 100 ° C, stirred for 1.5 hours, filtered through celite, and the solvent was evaporated to ethyl ether (250 mL). The organic phase was dried and filtered. 4-Phenoxyaniline (22.0 g, yield 83%).
MS m/z(ESI):300.1[M+H] + MS m/z (ESI): 300.1 [M+H] +
第六步:N-(3-溴-4-(2,4-二氟苯氧基)苯基)乙磺酰胺的制备Step 6: Preparation of N-(3-bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide
Figure PCTCN2018073989-appb-000032
Figure PCTCN2018073989-appb-000032
将3-溴-4-苯氧基苯胺(10g,33.44mmol)溶于二氯甲烷(80mL)冰浴下加入乙磺酰氯(5.52g,43.48mmol)、吡啶(5.28g,66.88mmol),室温搅拌过夜,有机相用盐酸(2M,100mL×2)洗,水(100mL×2)洗,饱和食盐水(100mL)洗,无水硫酸钠干燥,浓缩后柱层析(石油醚:乙酸乙酯=5:1,V/V)得到化合物N-(3-溴-4-(2,4-二氟苯氧基)苯基)乙磺酰胺(10.7g,产率82%)。Ethyl sulfonyl chloride (5.52 g, 43.48 mmol), pyridine (5.28 g, 66.88 mmol), rt, 3-bromo-4-phenoxyaniline (10 g, 33.44 mmol). After stirring overnight, the organic phase was washed with hydrochloric acid (2M, 100 mL×2), water (100 mL×2), washed with brine (100 mL), dried over anhydrous sodium sulfate =5:1, V/V) Compound N-(3-bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (10.7 g, yield 82%).
MS m/z(ESI):392.1.1[M+H] + MS m/z (ESI): 392.1.1 [M+H] +
第七步:N-(4-(2,4-二氟苯氧基)-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)乙磺酰胺的制备Step 7: N-(4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Preparation of phenyl) ethanesulfonamide
Figure PCTCN2018073989-appb-000033
Figure PCTCN2018073989-appb-000033
将N-(3-溴-4-(2,4-二氟苯氧基)苯基)乙磺酰胺(500mg,1.28mmol),4,4,4',4',5,5,5',5'-八甲基-2,2'-联(1,3,2-二噁硼戊环)(648mg,2.55mmol),1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷酰金刚烷(37mg,0.128mmol),三(二亚苄基丙酮)二钯(35mg,0.038mmol)和乙酸钾(275mg,2.82mmol)溶于1,4-二氧六环(20mL)。反应液在氮气保护80℃下,反应12小时,然后在105℃下反应5小时。将反应液蒸干,粗品柱分离(石油醚:乙酸乙酯=5:1,V/V)得到N-(4-(2,4-二氟苯氧基)苯基)乙磺酰胺和N-(4-(2,4-二氟苯氧基)-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)乙磺酰胺的混合物(500mg),直接用于下一步。N-(3-Bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (500 mg, 1.28 mmol), 4,4,4',4',5,5,5' , 5'-octamethyl-2,2'-linked (1,3,2-dioxaborolan) (648 mg, 2.55 mmol), 1,3,5,7-tetramethyl-6-phenyl -2,4,8-trioxa-6-phosphoryladamantane (37 mg, 0.128 mmol), tris(dibenzylideneacetone)dipalladium (35 mg, 0.038 mmol) and potassium acetate (275 mg, 2.82 mmol) In 1,4-dioxane (20 mL). The reaction solution was reacted at 80 ° C for 12 hours under nitrogen atmosphere, and then reacted at 105 ° C for 5 hours. The reaction solution was evaporated to dryness and then purified (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -(4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl) A mixture of ethanesulfonamide (500 mg) was used directly in the next step.
MS m/z(ESI):440.1[M+H] + MS m/z (ESI): 440.1 [M+H] +
第八步:N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙磺酰胺的制备Step 8: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Preparation of sulfonamide
Figure PCTCN2018073989-appb-000034
Figure PCTCN2018073989-appb-000034
将N-(4-(2,4-二氟苯氧基)-3-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯基)乙磺酰胺(395mg,0.9mmol),4-氯-6-甲基-1H-吡咯并[2,3-b]吡啶(100mg,0.6mmol),四三苯基膦钯(69mg,0.06mmol)和碳酸钾(414mg,3mmol)加入 到乙醇/甲苯/水(v/v/v=9:3:1,10mL)。反应液在氮气保护120℃下,微波反应0.5小时。将反应液蒸干,粗平使用制备板分离(石油醚:乙酸乙酯=1:1,V/V)得到N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙磺酰胺(190mg,产率71%)。N-(4-(2,4-difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene Ethyl sulfonamide (395 mg, 0.9 mmol), 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.6 mmol), tetratriphenylphosphine palladium (69 mg, 0.06) Methyl acetate and potassium carbonate (414 mg, 3 mmol) were added to ethanol/toluene/water (v/v/v = 9:3:1, 10 mL). The reaction solution was subjected to microwave reaction at 120 ° C for 0.5 hour under a nitrogen atmosphere. The reaction solution was evaporated to dryness, and then purified and purified using ethylamine (ethyl ether: ethyl acetate = 1:1, V/V) to give N-(4-(2,4-difluorophenoxy)-3-(6) Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)ethanesulfonamide (190 mg, yield 71%).
MS m/z(ESI):444.1[M+H] + MS m/z (ESI): 444.1 [M+H] +
第九步:4-(2-(2,4-二氟苯氧基)-5-(乙基磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 9: 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Preparation of pyridine-7-oxide
Figure PCTCN2018073989-appb-000035
Figure PCTCN2018073989-appb-000035
将间氯过氧苯甲酸(41mg,0.2mmol,85%)加入到N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙磺酰胺(60mg,0.14mmol)的四氢呋喃(2mL)溶液中。室温反应16小时后蒸干浓缩,粗品先使用反相柱制备(乙腈:水=2:3,V/V)得到粗品,再用制备板分离(二氯甲烷:甲醇=15:1),得到4-(2-(2,4-二氟苯氧基)-5-(乙基磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(12mg,产率19%)。m-Chloroperoxybenzoic acid (41 mg, 0.2 mmol, 85%) was added to N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2, 3-b]pyridin-4-yl)phenyl)ethanesulfonamide (60 mg, 0.14 mmol) in THF (2 mL). After reacting at room temperature for 16 hours, the mixture was evaporated to dryness. EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: 4-(2-(2,4-Difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide (12 mg, yield 19%).
1H NMR(400MHz,CDCl 3):δ12.06(br,1H),9.01(br,1H),7.43(d,J=2.4Hz,1H),7.31(dd,J=8.8Hz,2.4Hz,1H),7.21(d,J=3.2Hz,1H),7.13(d,J=7.6Hz,1H),6.87–6.77(m,2H),6.74(d,J=8.8Hz,1H),6.72–6.65(m,1H),6.47(d,J=3.2Hz,1H),3.12(q,J=7.4Hz,2H),2.57(s,3H),1.33(t,J=7.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.06 (br, 1H), 9.01 (br, 1H), 7.43 (d, J = 2.4Hz, 1H), 7.31 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.21 (d, J = 3.2 Hz, 1H), 7.13 (d, J = 7.6 Hz, 1H), 6.87 - 6.77 (m, 2H), 6.74 (d, J = 8.8 Hz, 1H), 6.72 - 6.65 (m, 1H), 6.47 (d, J = 3.2 Hz, 1H), 3.12 (q, J = 7.4 Hz, 2H), 2.57 (s, 3H), 1.33 (t, J = 7.4 Hz, 3H).
MS m/z(ESI):460.1[M+H] + MS m/z (ESI): 460.1 [M+H] +
实施例2Example 2
4-(5-(环丙磺酰氨基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(Cyclopropanesulfonylamino)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide
Figure PCTCN2018073989-appb-000036
Figure PCTCN2018073989-appb-000036
第一步:6-溴-4-氯-1H-吡咯并[2,3-b]吡啶的制备First step: Preparation of 6-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000037
Figure PCTCN2018073989-appb-000037
将(6-溴-4-氯-1H-吡咯并[2,3-b]吡啶-1-基)(苯基)甲酮(30.0g,89mmol)溶于甲醇(400mL),将氢氧化钠水溶液(1M,178mL)加入上述溶液中,室温下反应过夜后有大量白色固体析出,过滤,滤饼用水(20mL)洗涤,烘干,得6-溴-4-氯-1H-吡咯并[2,3-b]吡啶(17.0g,产率82.5%)。(6-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridin-1-yl)(phenyl)methanone (30.0 g, 89 mmol) dissolved in methanol (400 mL), sodium hydroxide Aqueous solution (1M, 178 mL) was added to the above solution. After a reaction at room temperature overnight, a large amount of white solid was precipitated, filtered, and the filter cake was washed with water (20 mL) and dried to give 6-bromo-4-chloro-1H-pyrrole[2 , 3-b]pyridine (17.0 g, yield 82.5%).
MS m/z(ESI):231.1[M+H] + MS m/z (ESI): 231.1 [M+H] +
第二步:6-溴-4-氯-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备Step 2: Preparation of 6-bromo-4-chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000038
Figure PCTCN2018073989-appb-000038
将6-溴-4-氯-1H-吡咯并[2,3-b]吡啶(17.0g,74mmol)溶于N,N-二甲基甲酰胺(50mL),用冰浴冷却到0℃,将氢化钠(5.9g,147mmol)分批加入上述溶液中,加完后在0℃下搅拌10分钟后将4-甲基磺酰氯(18.3g,96mmol)溶于N,N-二甲基甲酰胺(30mL)的溶液缓慢加入上述反应液中。室温搅拌1小时后用LC/MS检测反应完全。将反应液倒入冰水(500mL)中搅拌,有大量白色固体析出,过滤,滤饼用水(100mL)洗涤,烘干,得6-溴-4-氯-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(27.0g,产率94.7%)。6-Bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (17.0 g, 74 mmol) was dissolved in N,N-dimethylformamide (50 mL). Sodium hydride (5.9 g, 147 mmol) was added portionwise to the above solution, and after stirring for 10 minutes at 0 ° C, 4-methylsulfonyl chloride (18.3 g, 96 mmol) was dissolved in N,N-dimethyl A solution of the amide (30 mL) was slowly added to the above reaction solution. After stirring at room temperature for 1 hour, the reaction was completed by LC/MS. The reaction solution was poured into ice water (500 mL) and stirred, a large white solid was precipitated, filtered, and the filter cake was washed with water (100 mL) and dried to give 6-bromo-4-chloro-1-toluenesulfonyl-1H-pyrrole And [2,3-b]pyridine (27.0 g, yield 94.7%).
MS m/z(ESI):385.0[M+H] + MS m/z (ESI): 385.0 [M+H] +
第三步:4-氯-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备The third step: preparation of 4-chloro-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000039
Figure PCTCN2018073989-appb-000039
将6-溴-4-氯-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(15.5g,40mmol)溶于四氢呋喃(150mL),加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(1.46g,2mmol),置换氮气,在冰浴条件下滴加二甲基锌(20mL,1M甲苯溶液),滴加完毕后加热到70℃反应过夜,LC/MS检测反应完全。向反应液中加入水(400mL),用乙酸乙酯(300mL)萃取,有机相用饱和食盐水(300mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=10:1,V/V)得4-氯-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(11.5g,产率89%)。6-Bromo-4-chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (15.5 g, 40 mmol) was dissolved in tetrahydrofuran (150 mL) and [1,1'-bis (two) Phenylphosphino)ferrocene]palladium dichloride (1.46 g, 2 mmol), replacing nitrogen, adding dimethyl zinc (20 mL, 1 M solution in toluene) under ice bath, heating to 70 ° C after completion of the addition. The reaction was carried out overnight, and the reaction was completed by LC/MS. Water (400 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (300 mL). Ethyl ester = 10:1, V/V) gave 4-chloro-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (11.5 g, yield 89%).
1H NMR(400MHz,DMSO-d 6):δ8.05–8.03(d,J=8.4Hz,2H),7.90(d,J=4.0 Hz,1H),7.44-7.42(d,J=8.0Hz,2H),7.35(s,1H),6.79(d,J=4.0Hz,1H),2.56(s,3H),2.35(s,3H)。 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.05 - 8.03 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 4.0 Hz, 1H), 7.44 - 7.42 (d, J = 8.0 Hz) , 2H), 7.35 (s, 1H), 6.79 (d, J = 4.0 Hz, 1H), 2.56 (s, 3H), 2.35 (s, 3H).
MS m/z(ESI):321.1[M+H] + MS m/z (ESI): 321.1 [M+H] +
第四步:6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备The fourth step: 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrole Preparation of [2,3-b]pyridine
Figure PCTCN2018073989-appb-000040
Figure PCTCN2018073989-appb-000040
将4-氯-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(6.0g,18.8mmol),4,4,4',4',5,5,5',5'-八甲基-2,2'-联(1,3,2-二噁硼戊环)(7.6g,30mmol),醋酸钯(140mg,0.63mmol),[1,1'-联苯基]-3-基二环己基磷烷(438mg,1.25mmol),乙酸钾(9.2g,93.8mmol)溶于1,4-二氧六环(100mL),置换氮气,加热到90℃搅拌过夜,LC/MS检测反应完全。向反应液中加入水(200mL),用乙酸乙酯(200mL)萃取,有机相用饱和食盐水(200mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=10:1,V/V)得6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(5.5g,产率71.2%)。4-Chloro-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (6.0 g, 18.8 mmol), 4,4,4',4',5,5, 5',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolan) (7.6 g, 30 mmol), palladium acetate (140 mg, 0.63 mmol), [1,1' -biphenyl]-3-yldicyclohexylphosphane (438 mg, 1.25 mmol), potassium acetate (9.2 g, 93.8 mmol) dissolved in 1,4-dioxane (100 mL), replaced with nitrogen, heated to 90 After stirring at ° C overnight, the reaction was complete by LC/MS. Water (200 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (200 mL). Ethyl ester = 10:1, V/V) gives 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 -Tosyl-1H-pyrrolo[2,3-b]pyridine (5.5 g, yield 71.2%).
MS m/z(ESI)=413.1[M+H] + MS m/z (ESI) = 413.1 [M+H] +
第五步:4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯胺的制备Step 5: 4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline Preparation
Figure PCTCN2018073989-appb-000041
Figure PCTCN2018073989-appb-000041
将3-溴-4-(2,4-二氟苯氧基)苯胺(2.0g,6.67mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(2.75g,6.67mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(284mg,0.38mmol),碳酸钾(1.34g,9.7mmol)溶于1,4-二氧六环(16mL)和水(4mL)的混合物,在氮气保护下,100℃反应搅拌4小时,反应完全,将反应液倒入水中(50mL),用乙酸乙酯萃取(50mL×2),合并有机相,用水洗(100mL),饱和食盐水洗(100mL)后用无水硫酸钠干燥,浓缩后用柱层析(石油醚:乙酸乙酯=1:1,V/V)得到化合物4-(2,4-二氟苯氧基)-3-(6- 甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯胺(1.9g,产率56%)。3-Bromo-4-(2,4-difluorophenoxy)phenylamine (2.0 g, 6.67 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (2.75 g, 6.67 mmol), [1,1'-bis(diphenyl) a phosphinyl)ferrocene]palladium dichloride (284 mg, 0.38 mmol), potassium carbonate (1.34 g, 9.7 mmol) in a mixture of 1,4-dioxane (16 mL) and water (4 mL) Under a nitrogen atmosphere, the reaction was stirred at 100 ° C for 4 hours, and the reaction was completed. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (50 mL×2), and the organic phase was combined, washed with water (100 mL), and brine (100 mL) After drying with anhydrous sodium sulfate, and concentrated by column chromatography ( petroleum ether: ethyl acetate = 1:1, V/V) to give compound 4-(2,4-difluorophenoxy)-3- 6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenylamine (1.9 g, yield 56%).
MS m/z(ESI):506.1[M+H] +MS m/z (ESI): 506.1 [M+H] + .
第六步:N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)环丙磺酰胺的制备Step 6: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4- Preparation of phenyl)phenylpropanesulfonamide
Figure PCTCN2018073989-appb-000042
Figure PCTCN2018073989-appb-000042
将4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯胺(100mg,0.198mmol)溶于二氯甲烷(2mL)中,冰浴下加入环丙磺酰氯(36mg,0.257mmol),吡啶(31mg,0.394mmol),搅拌反应过夜,用饱和氯化铵水溶液(2mL)淬灭,将反应液旋干,加入20mL的水,然后用乙酸乙酯萃取(20mL×2),合并有机相,依次用水(40mL)和饱和食盐水(40mL)洗涤,并用无水硫酸钠干燥,浓缩后柱层析(石油醚:乙酸乙酯=3:1,V/V)得到N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)环丙磺酰胺(93mg,产率77%)。4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline (100 mg, 0.198 mmol) was dissolved in methylene chloride (2 mL). EtOAc EtOAc (EtOAc (EtOAc) The mixture was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj After concentration, column chromatography (petroleum ether: ethyl acetate = 3:1, V/V) afforded N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluene Sulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)cyclopropanesulfonamide (93 mg, yield 77%).
MS m/z(ESI):610.1[M+H] +MS m/z (ESI): 610.1 [M+H] + .
第七步:N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)环丙磺酰胺的制备Step 7: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) ring Preparation of propanesulfonamide
Figure PCTCN2018073989-appb-000043
Figure PCTCN2018073989-appb-000043
将N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)环丙磺酰胺(93.0mg,0.15mmol)溶于乙醇(3mL)中,室温下加入甲醇钠(25mg,0.46mmol),50℃下搅拌过夜,将反应液用饱和氯化铵水溶液(1mL)淬灭,然后用乙酸乙酯(20mL)萃取,合并有机相后用饱和碳酸氢钠水溶液(20mL)洗,水洗(20mL),饱和食盐水(20mL)洗,后用无水硫酸钠干燥,浓缩后用柱层析(石油醚:乙酸乙酯=1:1,V/V)得到化合物N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)环丙磺酰胺(40mg,产率58%)。N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene The propyl sulfonamide (93.0 mg, 0.15 mmol) was dissolved in ethanol (3 mL), sodium methoxide (25 mg, 0.46 mmol) was added at room temperature and stirred at 50 ° C overnight. After quenching, the mixture was extracted with EtOAc EtOAc EtOAc (EtOAc) After concentration, column chromatography (petroleum ether: ethyl acetate = 1:1, V/V) gave compound N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H) Pyrrolo[2,3-b]pyridin-4-yl)phenyl)cyclopropanesulfonamide (40 mg, yield 58%).
MS m/z(ESI):456.1[M+H] +MS m/z (ESI): 456.1 [M+H] + .
第八步:4-(5-(环丙磺酰氨基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 8: 4-(5-(Cyclopropanesulfonylamino)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Preparation of pyridine-7-oxide
Figure PCTCN2018073989-appb-000044
Figure PCTCN2018073989-appb-000044
将N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)环丙磺酰胺(40mg,0.087mmol)溶于THF(0.5mL)中,室温下加入间氯过氧苯甲酸(24mg,0.114mmol),室温下搅拌反应十分钟,用氯化铵的饱和水溶液(1mL)淬灭,加入水(10mL),然后用乙酸乙酯萃取(10mL×2),合并有机相后依次用碳酸氢钠饱和水溶液洗(20mL),水(20mL)和饱和食盐水(20mL)洗涤,并用无水硫酸钠干燥,浓缩后用制备色谱得到4-(5-(环丙磺酰氨基)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(25.5mg,产率62%)。N-(4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)cyclopropanesulfonamide (40 mg, 0.087 mmol) was dissolved in THF (0.5 mL). m. m. m. m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m After adding water (10 mL), and then extracting with ethyl acetate (10 mL×2), the organic phase was combined and washed with a saturated aqueous solution of sodium hydrogen carbonate (20 mL), water (20 mL) and brine (20 mL) Drying with sodium sulfate and concentrating to give 4-(5-(cyclopropylsulfonylamino)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrole [2,3-b]pyridine-7-oxide (25.5 mg, yield 62%).
1H NMR(400MHz,CDCl 3):δ11.72(s,1H),7.79(s,1H),7.49(s,1H),7.34(d,J=6.8Hz,2H),7.23(s,1H),7.00–6.86(m,2H),6.85–6.76(m,2H),6.59(d,J=2.9Hz,1H),2.69(s,3H),2.60-2.56(m,1H),1.24–1.17(m,2H),1.03–0.97(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ11.72 (s, 1H), 7.79 (s, 1H), 7.49 (s, 1H), 7.34 (d, J = 6.8Hz, 2H), 7.23 (s, 1H ), 7.00–6.86 (m, 2H), 6.85–6.76 (m, 2H), 6.59 (d, J = 2.9 Hz, 1H), 2.69 (s, 3H), 2.60-2.56 (m, 1H), 1.24– 1.17 (m, 2H), 1.03–0.97 (m, 2H).
MS m/z(ESI):472.1[M+H] +MS m/z (ESI): 4721. [M+H] + .
实施例3Example 3
4-(2-(2,4-二氟苯氧基)-5-((3,5-二甲基异噁唑)-4-磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(2,4-Difluorophenoxy)-5-((3,5-dimethylisoxazole)-4-sulfonylamino)phenyl)-6-methyl-1H- Pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000045
Figure PCTCN2018073989-appb-000045
第一步:N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)-3,5-二甲基异噁唑-4-磺酰胺的制备First step: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4- Of phenyl)-3,5-dimethylisoxazole-4-sulfonamide
Figure PCTCN2018073989-appb-000046
Figure PCTCN2018073989-appb-000046
以4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯胺为原料,参照实施例2第六步,以3,5-二甲基异噁唑-4-磺酰氯代替环丙磺酰氯,得到N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4- 基)苯基)-3,5-二甲基异噁唑-4-磺酰胺(110mg,产率87%)。Starting from 4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline, Referring to the sixth step of Example 2, replacing cyclopropylsulfonyl chloride with 3,5-dimethylisoxazole-4-sulfonyl chloride to obtain N-(4-(2,4-difluorophenoxy)-3- (6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-3,5-dimethylisoxazole-4-sulfonamide (110 mg , yield 87%).
MS m/z(ESI):645.1[M+H] +MS m/z (ESI): 645.1 [M+H] + .
第二步:N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)-3,5-二甲基异噁唑-4-磺酰胺的制备Second step: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)- Preparation of 3,5-dimethylisoxazole-4-sulfonamide
Figure PCTCN2018073989-appb-000047
Figure PCTCN2018073989-appb-000047
以N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)-3,5-二甲基异噁唑-4-磺酰胺为原料,参照实施例2第七步,得到化合物N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)-3,5-二甲基异噁唑-4-磺酰胺(70mg,产率83%)。N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene Starting from -3,5-dimethylisoxazole-4-sulfonamide as a starting material, referring to the seventh step of Example 2, the compound N-(4-(2,4-difluorophenoxy)-3- (6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-3,5-dimethylisoxazole-4-sulfonamide (70 mg, yield 83%) .
MS m/z(ESI):511.1[M+H] +MS m/z (ESI): 5121. [M+H] + .
第三步:4-(2-(2,4-二氟苯氧基)-5-((3,5-二甲基异噁唑)-4-磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧化的制备The third step: 4-(2-(2,4-difluorophenoxy)-5-((3,5-dimethylisoxazole)-4-sulfonylamino)phenyl)-6-A Preparation of 7-oxidation of yl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000048
Figure PCTCN2018073989-appb-000048
以N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)-3,5-二甲基异噁唑-4-磺酰胺为原料,参照实施例2第八步,得到4-(2-(2,4-二氟苯氧基)-5-((3,5-二甲基异噁唑)-4-磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(30.1mg,产率42%)。N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-3,5 - dimethyl isoxazole-4-sulfonamide as a starting material, and referring to the eighth step of Example 2, 4-(2-(2,4-difluorophenoxy)-5-((3,5-di) Methylisoxazole)-4-sulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (30.1 mg, yield 42%).
1H NMR(400MHz,CDCl 3):δ11.56(s,1H),9.05(s,1H),7.33-7.31(m,2H),7.21–7.10(m,2H),6.95–6.85(m,2H),6.78(dd,J=14.8,8.8Hz,2H),6.39(s,1H),2.66(s,3H),2.47(s,3H),2.32(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.56 (s, 1H), 9.05 (s, 1H), 7.33-7.31 (m, 2H), 7.21-7.10 (m, 2H), 6.95-6.85 (m, 2H), 6.78 (dd, J = 14.8, 8.8 Hz, 2H), 6.39 (s, 1H), 2.66 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H).
MS m/z(ESI):527.1[M+H] +. MS m/z (ESI): 527.1 [M+H] + .
实施例4Example 4
4-(2-(2,4-二氟苯氧基)-5-((1-甲基乙基)磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(2,4-difluorophenoxy)-5-((1-methylethyl)sulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000049
Figure PCTCN2018073989-appb-000049
第一步:N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)丙烷-2-磺酰胺的制备First step: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4- Of phenyl)propane-2-sulfonamide
Figure PCTCN2018073989-appb-000050
Figure PCTCN2018073989-appb-000050
以4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯胺为原料,参照实施例2第六步,以丙烷-2-磺酰氯代替环丙磺酰氯,得到N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)丙烷-2-磺酰胺(110mg,产率91%)。Starting from 4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline, Referring to the sixth step of Example 2, substituting propane-2-sulfonyl chloride for cyclopropanesulfonyl chloride to obtain N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluene) Sulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)propane-2-sulfonamide (110 mg, yield 91%).
MS m/z(ESI):612.1[M+H] +. MS m/z (ESI): 6121. [M+H] + .
第二步:N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)丙烷-2-磺酰胺的制备Second step: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)propane Preparation of -2-sulfonamide
Figure PCTCN2018073989-appb-000051
Figure PCTCN2018073989-appb-000051
以N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)丙烷-2-磺酰胺为原料,参照实施例2第七步,得到化合物N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)丙烷-2-磺酰胺(69mg,产率84%)。N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene The propane-2-sulfonamide was used as a starting material. Referring to the seventh step of Example 2, the compound N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrole was obtained. [2,3-b]pyridin-4-yl)phenyl)propane-2-sulfonamide (69 mg, yield 84%).
MS m/z(ESI):458.1[M+H] +MS m/z (ESI): 458.1 [M+H] + .
第三步:4-(2-(2,4-二氟苯氧基)-5-((1-甲基乙基)磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧化的制备Third step: 4-(2-(2,4-difluorophenoxy)-5-((1-methylethyl)sulfonylamino)phenyl)-6-methyl-1H-pyrrolo[ Preparation of 2,3-b]pyridine 7-oxidation
Figure PCTCN2018073989-appb-000052
Figure PCTCN2018073989-appb-000052
以N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)丙烷-2-磺酰胺为原料,参照实施例2第八步,得到4-(2-(2,4-二氟苯氧基)-5-((1-甲基乙基)磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧化物(27.6mg,产率39%)。 1H NMR(400MHz,DMSO-d 6):δ12.38(s,1H),9.84(s,1H),7.47(d,J=2.7Hz,1H),7.42–7.34(m,2H),7.29(dd,J=8.9,2.7Hz,1H),7.24(s,1H),7.12(td,J=9.2,5.6Hz,1H),7.05–6.89(m,2H),6.47(d,J=3.3Hz,1H),3.26(q,J=6.8Hz),2.52(s,3H),1.27(d,J=6.8Hz,6H). N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)propane-2- Sulfonamide was used as the starting material. Referring to the eighth step of Example 2, 4-(2-(2,4-difluorophenoxy)-5-((1-methylethyl)sulfonylamino)phenyl)- 6-Methyl-1H-pyrrolo[2,3-b]pyridine 7-oxide (27.6 mg, yield 39%). 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.38 (s, 1H), 9.84 (s, 1H), 7.47 (d, J = 2.7 Hz, 1H), 7.42 - 7.34 (m, 2H), 7.29 (dd, J=8.9, 2.7 Hz, 1H), 7.24 (s, 1H), 7.12 (td, J=9.2, 5.6 Hz, 1H), 7.05–6.89 (m, 2H), 6.47 (d, J=3.3) Hz, 1H), 3.26 (q, J = 6.8 Hz), 2.52 (s, 3H), 1.27 (d, J = 6.8 Hz, 6H).
MS m/z(ESI):474.1[M+H] +. MS m/z (ESI): 474.1 [M+H] + .
实施例5Example 5
4-(2-(2,4-二氟苯氧基)-5-((2,2,2-三氟乙基)磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(2,4-difluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl-1H-pyrrolo[ 2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000053
Figure PCTCN2018073989-appb-000053
第一步:4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯胺First step: 4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline
Figure PCTCN2018073989-appb-000054
Figure PCTCN2018073989-appb-000054
室温下将4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯胺(0.065g,0.13mmol)溶解于乙醇(5mL)中,然后将甲醇钠(0.014g,0.26mmol)加入到反应体系中,加热至50℃,反应过夜。反应结束后,将乙醇旋干,残留物用乙酸乙酯20(mL)溶解,盐水(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,得粗产物4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯胺(0.04g,白色固体,产率89%)。4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline (at room temperature) 0.065 g, 0.13 mmol) was dissolved in ethanol (5 mL), then sodium methoxide (0.014 g, 0.26 mmol) was added to the reaction system and heated to 50 ° C overnight. After the completion of the reaction, the ethanol was evaporated to dryness. EtOAc mjjjjjjjjjjjjjjjjjjj , 4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenylamine (0.04 g, white solid, yield 89%).
MS m/z(ESI):352.1[M+H] +. MS m/z (ESI): 3521. [M+H] + .
第二步:N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)-2,2,2-三氟乙烷-1-磺酰胺Second step: N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)- 2,2,2-trifluoroethane-1-sulfonamide
Figure PCTCN2018073989-appb-000055
Figure PCTCN2018073989-appb-000055
冰浴下将吡啶(0.018g,0.228mmol)和4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯胺(0.040g,0.114mmol)溶解于二氯甲烷(8mL)中,然后将2,2,2-三氟乙基磺酰氯(0.042g,0.228mmol)加入到反应体系中,室温搅拌过夜。 反应液用二氯甲烷(30mL)稀释,饱和碳酸氢钠溶液(10mL)洗涤,盐水(10mL)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,得粗产物N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)-2,2,2-三氟乙烷-1-磺酰胺(0.06g)直接用于下一步反应。Pyridine (0.018 g, 0.228 mmol) and 4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridine-4- The aniline (0.040 g, 0.114 mmol) was dissolved in dichloromethane (8 mL), then 2,2,2-trifluoroethylsulfonyl chloride (0.042 g, 0.228 mmol) was added to the reaction system and stirred at room temperature overnight. . The reaction mixture was diluted with methylene chloride (30 mL). EtOAc (EtOAc) 2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2,2,2-trifluoroethane 1-sulfonamide (0.06 g) was used directly in the next reaction.
MS m/z(ESI):498.1[M+H] +. MS m/z (ESI): 498.1 [M+H] + .
第三步:4-(2-(2,4-二氟苯氧基)-5-((2,2,2-三氟乙基)磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物The third step: 4-(2-(2,4-difluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl-1H -pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000056
Figure PCTCN2018073989-appb-000056
室温下将粗产物N-(4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)-2,2,2-三氟乙烷-1-磺酰胺(0.04g,0.08mmol)溶解于二氯甲烷(8mL)中,然后将间氯过氧苯甲酸(0.02g,85%,0.097mmol)加入到反应液中,室温反应半小时。反应液用二氯甲烷(20mL)稀释,有机相用饱和碳酸氢钠溶液(10mL)洗涤,盐水(10mL)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用制备反相色谱分离得4-(2-(2,4-二氟苯氧基)-5-((2,2,2-三氟乙基)磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.015g,白色固体,产率:36%)。The crude product N-(4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) -2,2,2-Trifluoroethane-1-sulfonamide (0.04 g, 0.08 mmol) was dissolved in dichloromethane (8 mL), then m-chloroperoxybenzoic acid (0.02 g, 85%, 0.097 mmol) ) was added to the reaction solution and allowed to react at room temperature for half an hour. The reaction mixture was diluted with methylene chloride (20 mL). EtOAc (EtOAc)EtOAc. Chromatography to give 4-(2-(2,4-difluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl-1H- Pyrrolo[2,3-b]pyridine-7-oxide (0.015 g, white solid, yield: 36%).
MS m/z(ESI):514.1[M+H] +. MS m/z (ESI): 514.1 [M+H] + .
1HNMR(400MHz,CD 3OD):δ11.73(br,1H),9.12(br,1H),7.38-7.36(m,2H),7.24(s,1H),7.17(s,1H),6.98-6.88(m,2H),6.83-6.78(m,2H),6.50(d,J=2.8Hz,1H),3.96(t,J=8.8Hz,2H),2.65(s,3H). 1 H NMR (400 MHz, CD 3 OD): δ 11.73 (br, 1H), 9.12 (br, 1H), 7.38-7.36 (m, 2H), 7.24 (s, 1H), 7.17 (s, 1H), 6.98 -6.88 (m, 2H), 6.83-6.78 (m, 2H), 6.50 (d, J = 2.8 Hz, 1H), 3.96 (t, J = 8.8 Hz, 2H), 2.65 (s, 3H).
实施例6Example 6
4-(2-(4-溴-2-氟苯氧基)-5-(乙基磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-Bromo-2-fluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 -oxide
Figure PCTCN2018073989-appb-000057
Figure PCTCN2018073989-appb-000057
第一步:4-(2-氟-5-硝基苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备First step: Preparation of 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000058
Figure PCTCN2018073989-appb-000058
将6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(500mg,1.21mmol),2-溴-1-氟-4-硝基苯(533mg,2.42mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(88.5mg,0.12mmol),碳酸钾(500mg,3.63mmol)溶于1,4-二氧六环(10mL)和水(3mL)的混合物中,在氮气保护下100℃反应4小时后用LC/MS检测反应完全。向反应液中加入水(100mL),用乙酸乙酯(100mL×2)萃取,有机相用饱和食盐水(100mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=2:1,V/V)得4-(2-氟-5-硝基苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(400mg,产率78%)。6-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2 , 3-b]pyridine (500 mg, 1.21 mmol), 2-bromo-1-fluoro-4-nitrobenzene (533 mg, 2.42 mmol), [1,1'-bis(diphenylphosphino)ferrocene Palladium dichloride (88.5 mg, 0.12 mmol), potassium carbonate (500 mg, 3.63 mmol) dissolved in a mixture of 1,4-dioxane (10 mL) and water (3 mL). After 4 hours, the reaction was completed by LC/MS. Water (100 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (100 mL×2). : ethyl acetate = 2:1, V/V) gave 4-(2-fluoro-5-nitrophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b Pyridine (400 mg, yield 78%).
MS m/z(ESI):426.1[M+H] + MS m/z (ESI): 426.1 [M+H] +
第二步:4-(2-(4-溴-2-氟苯氧基)-5-硝基苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备Second step: 4-(2-(4-bromo-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3- b] Preparation of pyridine
Figure PCTCN2018073989-appb-000059
Figure PCTCN2018073989-appb-000059
将4-(2-氟-5-硝基苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(400mg,0.94mmol),4-溴-2-氟苯酚(533mg,2.42mmol)溶于二甲基亚砜(5mL),加入碳酸铯(368mg,1.13mmol),加热到100℃搅拌1小时,LC/MS检测反应完全。向反应液中加入水(100mL),用乙酸乙酯(50mL×2)萃取,有机相用饱和碳酸钠溶液(50mL×2)和饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,浓缩得4-(2-(4-溴-2-氟苯氧基)-5-硝基苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(500mg,产率89%)。4-(2-Fluoro-5-nitrophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (400 mg, 0.94 mmol), 4-bromo- 2-Fluorophenol (533 mg, 2.42 mmol) was dissolved in dimethyl sulfoxide (5 mL), cesium carbonate (368 mg, 1.13 mmol) was added, and the mixture was stirred at 100 ° C for 1 hour, and the reaction was confirmed by LC/MS. Water (100 mL) was added to the reaction mixture, and the mixture was evaporated to ethyl acetate (50 mL?? 4-(2-(4-Bromo-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (500 mg, yield 89%).
MS m/z(ESI):596.0[M+H] + MS m/z (ESI): 596.0 [M+H] +
第三步:4-(2-(4-溴-2-氟苯氧基)-5-硝基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Third step: Preparation of 4-(2-(4-bromo-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000060
Figure PCTCN2018073989-appb-000060
将4-(2-(4-溴-2-氟苯氧基)-5-硝基苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b] 吡啶(500mg,0.84mmol)溶于叔丁醇(15mL),将氢氧化钾水溶液(3M,8mL)加入上述溶液中,加热到75℃搅拌过夜。反应液用乙酸乙酯(50mL×2)萃取,有机相用饱和食盐水(50mL×2)洗涤,用无水硫酸钠干燥,浓缩得4-(2-(4-溴-2-氟苯氧基)-5-硝基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(300mg,产率81%).4-(2-(4-Bromo-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 0.84 mmol) was dissolved in tert-butanol (15 mL), and aqueous potassium hydroxide (3M, 8 mL) was added to the above solution, and the mixture was stirred at 75 ° C overnight. The reaction mixture was extracted with ethyl acetate (50 mL×2). 5-)-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (300 mg, yield 81%).
MS m/z(ESI):442.0[M+H] + MS m/z (ESI): 442.0 [M+H] +
第四步:4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯胺的制备Fourth step: Preparation of 4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline
Figure PCTCN2018073989-appb-000061
Figure PCTCN2018073989-appb-000061
将4-(2-(4-溴-2-氟苯氧基)-5-硝基苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(300mg,0.68mmol)溶于四氢呋喃(10mL)、乙醇(10mL)和水(3mL)的混合物,将还原铁粉(280mg,5mmol),氯化铵(265mg,5mmol)加入上述溶液中,加热到100℃搅拌1小时。过滤,滤渣用乙酸乙酯(50mL)洗涤,滤液用饱和食盐水(50mL)洗涤后用无水硫酸钠干燥,浓缩得4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯胺(230mg,产率82.1%)。4-(2-(4-Bromo-2-fluorophenoxy)-5-nitrophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.68 mmol) A mixture of tetrahydrofuran (10 mL), ethanol (10 mL) and water (3 mL) was added, and reduced iron powder (280 mg, 5 mmol), ammonium chloride (265 mg, 5 mmol) was added to the above solution, and the mixture was stirred at 100 ° C for 1 hour. Filtration, the residue was washed with ethyl acetate (50 mL), EtOAc (EtOAc) Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline (230 mg, yield 82.1%).
MS m/z(ESI):412.0[M+H] + MS m/z (ESI): 412.0 [M+H] +
第五步:N-(4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙磺酰胺的制备The fifth step: N-(4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Preparation of ethanesulfonamide
Figure PCTCN2018073989-appb-000062
Figure PCTCN2018073989-appb-000062
将4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯胺(100mg,0.24mmol)溶于二氯甲烷(5mL),加入乙基磺酰氯(88mg,0.69mmol),吡啶(0.3mL),室温下搅拌过夜。向反应液中加乙酸乙酯(50mL)稀释,有机相用饱和氯化铵溶液(50mL×2)和饱和食盐水(50mL×2)洗涤,用无水硫酸钠干燥,浓缩得N-(4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙磺酰胺(70mg,产率57%).Dissolving 4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenylamine (100 mg, 0.24 mmol) Dichloromethane (5 mL) was added, EtOAc (EtOAc, m. The reaction mixture was diluted with ethyl acetate (50 mL). EtOAc (EtOAc m. -(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)ethanesulfonamide (70 mg, yield 57%).
MS m/z(ESI):504.0[M+H] + MS m/z (ESI): 504.0 [M+H] +
第六步:4-(2-(4-溴-2-氟苯氧基)-5-(乙基磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 6: 4-(2-(4-Bromo-2-fluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b Preparation of pyridine-7-oxide
Figure PCTCN2018073989-appb-000063
Figure PCTCN2018073989-appb-000063
将N-(4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙磺酰胺(70mg,0.14mmol)溶于四氢呋喃(2mL),加入间氯过氧苯甲酸(42mg,0.21mmol),室温搅拌30分钟。向反应液中加入乙酸乙酯(50mL),用饱和碳酸钠溶液(30mL×2)洗涤,然后用饱和食盐水(30mL)洗涤,后用无水硫酸钠干燥,浓缩后通过硅胶制备色谱分离(二氯甲烷:甲醇=10:1,V/V)纯化得到4-(2-(4-溴-2-氟苯氧基)-5-(乙基磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(10.0mg,产率13.7%)。N-(4-(4-Bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)ethanesulfonamide (70 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 mL), and m-chloroperoxybenzoic acid (42 mg, 0.21 mmol) was added and stirred at room temperature for 30 min. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium sulfate (30 mL×2) and then washed with brine (30 mL). Purification of dichloromethane (methanol = 10:1, V/V) gave 4-(2-(4-bromo-2-fluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6- Base-1H-pyrrolo[2,3-b]pyridine-7-oxide (10.0 mg, yield 13.7%).
1H NMR(400MHz,CDCl 3):δ11.75(s,1H),8.79(s,1H),7.44(s,1H),7.38–7.36(d,J=8.8Hz,1H),7.26-7.23(m,2H),7.15(s,1H),7.12-7.10(d,J=8.8Hz,1H),6.91-6.88(d,J=8.8Hz,1H),6.77-6.75(t,J=8.8Hz,1H),6.51(d,J=2.8Hz,1H),3.23(q,J=7.2Hz,2H),2.63(s,3H),1.43-1.41(t,J=3.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.75 (s, 1H), 8.79 (s, 1H), 7.44 (s, 1H), 7.38-7.36 (d, J = 8.8Hz, 1H), 7.26-7.23 (m, 2H), 7.15 (s, 1H), 7.12-7.10 (d, J = 8.8 Hz, 1H), 6.91-6.88 (d, J = 8.8 Hz, 1H), 6.77-6.75 (t, J = 8.8 Hz, 1H), 6.51 (d, J = 2.8 Hz, 1H), 3.23 (q, J = 7.2 Hz, 2H), 2.63 (s, 3H), 1.43-1.41 (t, J = 3.6 Hz, 3H).
MS m/z(ESI):520.0[M+H] + MS m/z (ESI): 520.0 [M+H] +
实施例7Example 7
4-(2-(4-溴-2-氟苯氧基)-5-((2,2,2-三氟乙基)磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-Bromo-2-fluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl-1H-pyrrole [2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000064
Figure PCTCN2018073989-appb-000064
第一步:N-(4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)-2,2,2-三氟乙烷-1-磺酰胺的制备First step: N-(4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) -2,2,2-Trifluoroethane-1-sulfonamide preparation
Figure PCTCN2018073989-appb-000065
Figure PCTCN2018073989-appb-000065
以4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯胺为原料,参照实施例6第五步,用2,2,2-三氟乙基磺酰氯取代乙基磺酰氯,得N-(4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)-2,2,2-三氟乙烷-1-磺酰胺(60.0mg,产率45.0%)。Taking 4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)aniline as a starting material, refer to Example 6 Five steps, substituting 2,2,2-trifluoroethylsulfonyl chloride for ethylsulfonyl chloride to give N-(4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H Pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2,2,2-trifluoroethane-1-sulfonamide (60.0 mg, yield 45.0%).
MS m/z(ESI):558.0[M+H] + MS m/z (ESI): 558.0 [M+H] +
第二步:4-(2-(4-溴-2-氟苯氧基)-5-((2,2,2-三氟乙基)磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Second step: 4-(2-(4-bromo-2-fluorophenoxy)-5-((2,2,2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl- Preparation of 1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000066
Figure PCTCN2018073989-appb-000066
以N-(4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)-2,2,2-三氟乙烷-1-磺酰胺为原料,参照实施例6第六步,得4-(2-(4-溴-2-氟苯氧基)-5-((2,2,2-三氟乙基)磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(18.5mg,产率35.8%)。N-(4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)-2, Using 2,2-trifluoroethane-1-sulfonamide as the starting material, referring to the sixth step of Example 6, 4-(2-(4-bromo-2-fluorophenoxy)-5-((2,2) , 2-trifluoroethyl)sulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (18.5 mg, yield 35.8%).
1H NMR(400MHz,CDCl 3):δ12.29(s,1H),10.11(s,1H),7.44–7.42(dd,J=8.8Hz,2.0Hz,1H),7.32(s,1H),7.24(d,J=2.0Hz,1H),7.18(d,J=2.4Hz,1H),7.14-7.12(d,J=8.8Hz,1H),7.11(s,1H),6.89-6.87(d,J=8.8Hz,1H),6.80-6.76(t,J=8.8Hz,1H),6.42(d,J=2.8Hz,1H),4.04-3.97(m,2H),2.61(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ12.29 (s, 1H), 10.11 (s, 1H), 7.44-7.42 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.32 (s, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.14 - 7.12 (d, J = 8.8 Hz, 1H), 7.11 (s, 1H), 6.89-6.87 (d , J = 8.8 Hz, 1H), 6.80-6.76 (t, J = 8.8 Hz, 1H), 6.42 (d, J = 2.8 Hz, 1H), 4.04-3.97 (m, 2H), 2.61 (s, 3H) .
MS m/z(ESI):574.0[M+H] + MS m / z (ESI): 574.0 [M + H] +
实施例8Example 8
4-(5-(乙基磺酰氨基)-2-(((1r,4r)-4-甲基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000067
Figure PCTCN2018073989-appb-000067
第一步:2-溴-1-(((1r,4r)-4-甲基环己基)氧代)-4-硝基苯的制备First step: Preparation of 2-bromo-1-(((1r,4r)-4-methylcyclohexyl)oxo)-4-nitrobenzene
Figure PCTCN2018073989-appb-000068
Figure PCTCN2018073989-appb-000068
将(1r,4r)-4-甲基环己烷-1-醇(1.6g,13.6mmol)溶于N,N-二甲基甲酰胺(50mL),冰浴下用氮气保护加入氢化钠(0.5g,13.6mmol),搅拌半小时后加入2-溴-1-氟-4-硝基苯(2.0g,9mmol),反应在室温下搅拌过夜。加水(100mL)淬灭反应,有黄色固体析出,将混合物过滤,固体用水洗(20mL×2),收集固体旋干后得2-溴-1-(((1r,4r)-4-甲基环己基)氧代)-4-硝基苯(2.8g,产率98%)。(1r,4r)-4-methylcyclohexane-1-ol (1.6 g, 13.6 mmol) was dissolved in N,N-dimethylformamide (50 mL). 0.5 g, 13.6 mmol), after stirring for half an hour, 2-bromo-1-fluoro-4-nitrobenzene (2.0 g, 9 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was quenched by the addition of water (100 mL), and then the mixture was evaporated. The mixture was filtered. The mixture was filtered and washed with water (20mL×2). Cyclohexyl)oxo)-4-nitrobenzene (2.8 g, yield 98%).
1H NMR(400MHz,CDCl 3):δ8.39(d,J=2.8Hz,1H),8.09(dd,J=9.2Hz,2.8Hz,1H),6.87(d,J=9.2Hz,1H),4.32–4.22(m,1H),2.12–2.04(m,2H),1.81– 1.72(m,2H),1.52–1.46(m,2H),1.46–1.38(m,1H),1.08–0.96(m,2H),0.88(d,J=6.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ8.39 (d, J = 2.8Hz, 1H), 8.09 (dd, J = 9.2Hz, 2.8Hz, 1H), 6.87 (d, J = 9.2Hz, 1H) , 4.32–4.22 (m, 1H), 2.12–2.04 (m, 2H), 1.81– 1.72 (m, 2H), 1.52–1.46 (m, 2H), 1.46–1.38 (m, 1H), 1.08–0.96 ( m, 2H), 0.88 (d, J = 6.4 Hz, 3H).
第二步:3-溴-4-(((1r,4r)-4-甲基环己基)氧代)苯胺的制备Second step: Preparation of 3-bromo-4-(((1r,4r)-4-methylcyclohexyl)oxo)aniline
Figure PCTCN2018073989-appb-000069
Figure PCTCN2018073989-appb-000069
将2-溴-1-(((1r,4r)-4-甲基环己基)氧代)-4-硝基苯(2.8g,8.9mmol)溶于乙醇(40mL),加入铁粉(2.5g,44.6mmol),氯化铵(2.4g,44.6mmol)和水(20mL),反应在90℃下搅拌2小时。反应液冷却至室温后过滤,将滤液旋干。粗产物用柱层析分离(石油醚:乙酸乙酯=30:1到2:1梯度冲洗)纯化得到3-溴-4-(((1r,4r)-4-甲基环己基)氧代)苯胺(2.0g,产率:79%)。2-Bromo-1-(((1r,4r)-4-methylcyclohexyl)oxo)-4-nitrobenzene (2.8 g, 8.9 mmol) was dissolved in ethanol (40 mL) and iron powder (2.5) g, 44.6 mmol), ammonium chloride (2.4 g, 44.6 mmol) and water (20 mL), and the mixture was stirred at 90 ° C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was dried. The crude product was purified by column chromatography ( petroleum ether: ethyl acetate = 30:1 to 2:1 gradient elution) to afford 3-bromo-4-(((1r,4r)-4-methylcyclohexyl) oxo Aniline (2.0 g, yield: 79%).
MS m/z(ESI):284.0[M+H] + MS m/z (ESI): 284.0 [M+H] +
第三步:N-(3-溴-4-(((1r,4r)-4-甲基环己基)氧代)苯基)乙磺酰胺的制备Third step: Preparation of N-(3-bromo-4-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)ethanesulfonamide
Figure PCTCN2018073989-appb-000070
Figure PCTCN2018073989-appb-000070
将3-溴-4-(((1r,4r)-4-甲基环己基)氧代)苯胺(2.0g,7mmol)溶于二氯甲烷(40mL),依次加入吡啶(2.8g,35mmol),乙磺酰氯(2.7g,21.0mmol),反应在室温下搅拌1小时后加入盐酸水溶液(1M,50mL),水相用二氯甲烷萃取(30mL×2),有机相经无水硫酸钠干燥,过滤,浓缩后得到化合物N-(3-溴-4-(((1r,4r)-4-甲基环己基)氧代)苯基)乙磺酰胺(2.0g,产率:76%)。3-Bromo-4-(((1r,4r)-4-methylcyclohexyl)oxy)aniline (2.0 g, 7 mmol) was dissolved in dichloromethane (40 mL), then pyridine (2.8 g, Ethyl sulfonyl chloride (2.7 g, 21.0 mmol) was stirred at room temperature for 1 hour, then aqueous hydrochloric acid (1M, 50 mL) was evaporated. Filtration and concentration gave the compound N-(3-bromo-4-(((1r,4r)-4-methylcyclohexyl)oxy)phenyl)ethanesulfonamide (2.0 g, yield: 76%) .
MS m/z(ESI):375.0[M] + MS m/z (ESI): 375.0 [M] +
第四步:N-(3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)-4-(((1r,4r)-4-甲基环己基)氧代)苯基)乙磺酰胺的制备The fourth step: N-(3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4) -Methylcyclohexyl)oxo)phenyl)ethanesulfonamide
Figure PCTCN2018073989-appb-000071
Figure PCTCN2018073989-appb-000071
将N-(3-溴-4-(((1r,4r)-4-甲基环己基)氧代)苯基)乙磺酰胺(0.4g,1.1mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(0.5g,1.3mmol),碳酸钾(350mg,2.8mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(80mg,0.1mmol)溶于1,4二氧六环(10mL)和水(2mL),反应在 氮气保护下90℃搅拌2小时。反应液冷却至室温后加入乙酸乙酯(50mL),然后用水洗(30mL),无水硫酸钠干燥,过滤,浓缩,粗品用柱层析分离(石油醚:乙酸乙酯=50:1至纯乙酸乙酯梯度冲洗)纯化得到化合物N-(3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)-4-(((1r,4r)-4-甲基环己基)氧代)苯基)乙磺酰胺(0.4g,产率:65%)。N-(3-Bromo-4-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)ethanesulfonamide (0.4 g, 1.1 mmol), 6-methyl-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.5g , 1.3 mmol), potassium carbonate (350 mg, 2.8 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (80 mg, 0.1 mmol) dissolved in 1,4 dioxane Ring (10 mL) and water (2 mL) were stirred and stirred at 90 ° C for 2 hr under nitrogen. After the reaction mixture was cooled to room temperature, ethyl acetate (50 mL) was evaporated, evaporated, evaporated. Purification by ethyl acetate gradient elution to give the compound N-(3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-((1r) 4r)-4-methylcyclohexyl)oxo)phenyl)ethanesulfonamide (0.4 g, yield: 65%).
MS m/z(ESI):582.2[M+H] + MS m/z (ESI): 582.2 [M+H] +
第五步:N-(3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(((1r,4r)-4-甲基环己基)氧代)苯基)乙磺酰胺的制备Step 5: N-(3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl) Preparation of oxo)phenyl)ethanesulfonamide
Figure PCTCN2018073989-appb-000072
Figure PCTCN2018073989-appb-000072
将N-(3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)-4-(((1r,4r)-4-甲基环己基)氧代)苯基)乙磺酰胺(0.4g,0.69mmol)和氢氧化钾(0.8g,13.8mmol)溶于叔丁醇(20mL)和水(2mL),反应在60℃下搅拌18小时。将反应液旋干,加入二氯甲烷(20mL),有机相经水洗(20mL),无水硫酸钠干燥,过滤,浓缩,得到化合物N-(3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(((1r,4r)-4-甲基环己基)氧代)苯基)乙磺酰胺(0.2g,产率:68%)。N-(3-(6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methyl) Cyclohexyl)oxo)phenyl)ethanesulfonamide (0.4 g, 0.69 mmol) and potassium hydroxide (0.8 g, 13.8 mmol) were dissolved in tert-butanol (20 mL) and water (2 mL), and the mixture was stirred at 60 ° C. 18 hours. The reaction mixture was dried with EtOAc (EtOAc) (EtOAcjjjjjjjjjjjjj 2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)ethanesulfonamide (0.2 g, yield: 68%).
MS m/z(ESI):428.1[M+H] + MS m / z (ESI): 428.1 [M + H] +
第六步:4-(5-(乙基磺酰氨基)-2-(((1r,4r)-4-甲基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 6: 4-(5-(ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000073
Figure PCTCN2018073989-appb-000073
将N-(3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(((1r,4r)-4-甲基环己基)氧代)苯基)乙磺酰胺(100mg,0.23mmol)和间氯过氧苯甲酸(95mg,0.46mmol)溶于四氢呋喃(4mL),反应在25℃下搅拌2小时。反应液浓缩后,粗品用高效液相色谱柱分离得到化合物4-(5-(乙基磺酰氨基)-2-(((1r,4r)-4-甲基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(11mg,产率:11%)。N-(3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl)oxo) Phenyl)ethanesulfonamide (100 mg, 0.23 mmol) and m-chloroperoxybenzoic acid (95 mg, 0.46 mmol) were dissolved in tetrahydrofuran (4 mL), and the mixture was stirred at 25 ° C for 2 hours. After the reaction mixture is concentrated, the crude product is separated by high performance liquid chromatography to give the compound 4-(5-(ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)oxy)phenyl) 6-Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (11 mg, yield: 11%).
1H NMR(400MHz,CD 3OD):δ7.30–7.29(m,2H),7.21(dd,J=8.8Hz,2.8 Hz,1H),7.17(s,1H),7.05(d,J=8.8Hz,1H),6.43(d,J=3.2Hz,1H),4.11–3.98(m,1H),2.99(q,J=7.2Hz,2H),2.60(s,3H),1.95–1.86(m,2H),1.64–1.52(m,2H),1.32–1.21(m,4H),1.18–1.08(m,2H),0.96–0.87(m,2H),0.78(d,J=6.4Hz,3H)。 1 H NMR (400 MHz, CD 3 OD): δ 7.30 - 7.29 (m, 2H), 7.21. (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.17 (s, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.43 (d, J = 3.2 Hz, 1H), 4.11 - 3.98 (m, 1H), 2.99 (q, J = 7.2 Hz, 2H), 2.60 (s, 3H), 1.95 - 1.86 ( m, 2H), 1.64 - 1.52 (m, 2H), 1.32 - 1.21 (m, 4H), 1.18 - 1.08 (m, 2H), 0.96 - 0.87 (m, 2H), 0.78 (d, J = 6.4 Hz, 3H).
MS m/z(ESI):444.1[M+H] +MS m/z (ESI): 444.1 [M+H] + .
实施例9Example 9
4-(5-(乙基磺酰氨基)-2-(((1r,4r)-4-甲基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000074
Figure PCTCN2018073989-appb-000074
第一步:2-溴-N-((1r,4r)-4-甲基环己基)-4-硝基苯胺的制备First step: Preparation of 2-bromo-N-((1r,4r)-4-methylcyclohexyl)-4-nitroaniline
Figure PCTCN2018073989-appb-000075
Figure PCTCN2018073989-appb-000075
将2-溴-1-氟-4-硝基苯(4.0g,18mmol),(1r,4r)-4-甲基环己烷-1-胺(6.2g,55mmol)和N,N-二异丙基乙胺(11.6g,90mmol)溶于N-甲基-2-吡咯烷酮(30mL),在130℃下搅拌18小时。反应液冷却至室温后加水(200mL),搅拌1小时,有黄色固体析出。将混合物过滤,固体用水洗,收集固体旋干后得2-溴-N-((1r,4r)-4-甲基环己基)-4-硝基苯胺(4.5g,产率79%)。2-Bromo-1-fluoro-4-nitrobenzene (4.0 g, 18 mmol), (1r, 4r)-4-methylcyclohexane-1-amine (6.2 g, 55 mmol) and N,N- Isopropylethylamine (11.6 g, 90 mmol) was dissolved in N-methyl-2-pyrrolidone (30 mL) and stirred at 130 ° C for 18 hours. After the reaction mixture was cooled to room temperature, water (200 mL) was added and stirred for 1 hour, and a yellow solid was precipitated. The mixture was filtered, and the solid was washed with water, and then evaporated to dryness to give the product of 2-bromo-N-((1r,4r)-4-methylcyclohexyl)-4-nitroaniline (4.5 g, yield 79%).
1H NMR(400MHz,CDCl 3):δ8.36(d,J=2.4Hz,1H),8.08(dd,J=9.2Hz,2.4Hz,1H),6.58(d,J=9.2Hz,1H),4.97(d,J=7.2Hz,1H),3.40–3.28(m,1H),2.17–2.07(m,2H),1.87–1.80(m,2H),1.50–1.40(m,1H),1.35–1.21(m,2H),1.17–1.03(m,2H),0.95(d,J=6.4Hz,3H)。 1 H NMR (400MHz, CDCl 3 ): δ8.36 (d, J = 2.4Hz, 1H), 8.08 (dd, J = 9.2Hz, 2.4Hz, 1H), 6.58 (d, J = 9.2Hz, 1H) , 4.97 (d, J = 7.2 Hz, 1H), 3.40 - 3.28 (m, 1H), 2.17 - 2.07 (m, 2H), 1.87 - 1.80 (m, 2H), 1.50 - 1.40 (m, 1H), 1.35 -1.21 (m, 2H), 1.17 - 1.03 (m, 2H), 0.95 (d, J = 6.4 Hz, 3H).
第二步:2-溴-N1-((1r,4r)-4-甲基环己基)苯-1,4-二胺的制备Second step: Preparation of 2-bromo-N1-((1r,4r)-4-methylcyclohexyl)benzene-1,4-diamine
Figure PCTCN2018073989-appb-000076
Figure PCTCN2018073989-appb-000076
将2-溴-N-((1r,4r)-4-甲基环己基)-4-硝基苯胺(4.5g,14.4mmol)溶于乙醇(100mL),加入铁粉(4g,72.0mmol),氯化铵(15.3g,0.3mol)和水(20mL),反应在90℃下搅拌2小时。反应液冷却至室温,过滤,浓缩滤液得粗品。粗品用柱层析分离(石油醚:乙酸乙酯=50:1到1:1梯度冲洗)纯化得到2-溴 -N1-((1r,4r)-4-甲基环己基)苯-1,4-二胺(4g,产率98%)。2-Bromo-N-((1r,4r)-4-methylcyclohexyl)-4-nitroaniline (4.5 g, 14.4 mmol) was dissolved in ethanol (100 mL) and iron powder (4 g, 72.0 mmol) was added. Ammonium chloride (15.3 g, 0.3 mol) and water (20 mL) were stirred at 90 ° C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was evaporated. The crude product was purified by column chromatography ( petroleum ether: ethyl acetate = 50:1 to 1:1 gradient) to afford 2-bromo-N1-((1r,4r)-4-methylcyclohexyl)benzene-1, 4-Diamine (4 g, yield 98%).
1H NMR(400MHz,CDCl 3):δ6.87(d,J=2.4Hz,1H),6.62–6.53(m,2H),3.40(br,3H),3.14–3.04(m,1H),2.13–2.03(m,2H),1.80–1.69(m,2H),1.47–1.32(m,1H),1.22–0.96(m,4H),0.92(d,J=6.4Hz,3H)。 1 H NMR (400MHz, CDCl 3 ): δ6.87 (d, J = 2.4Hz, 1H), 6.62-6.53 (m, 2H), 3.40 (br, 3H), 3.14-3.04 (m, 1H), 2.13 -2.03 (m, 2H), 1.80 - 1.69 (m, 2H), 1.47 - 1.32 (m, 1H), 1.22 - 0.96 (m, 4H), 0.92 (d, J = 6.4 Hz, 3H).
MS m/z(ESI):283.0,285.0[M+H] + MS m/z (ESI): 283.0, 285.0 [M+H] +
第三步:N-(3-溴-4-(((1r,4r)-4-甲基环己基)氨基)苯基)乙磺酰胺的制备Third step: Preparation of N-(3-bromo-4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)ethanesulfonamide
Figure PCTCN2018073989-appb-000077
Figure PCTCN2018073989-appb-000077
将2-溴-N1-((1r,4r)-4-甲基环己基)苯-1,4-二胺(4.0g,14mmol)溶于二氯甲烷(100mL),依次加入吡啶(3.3g,42mmol),乙磺酰氯(1.8g,14.0mmol),反应在室温下搅拌18小时。加入水(300mL),水相用二氯甲烷萃取(300mL),有机相经无水硫酸钠干燥,过滤,浓缩,粗品用柱层析分离(石油醚:乙酸乙酯=50:1至3:1梯度冲洗)纯化得到化合物N-(3-溴-4-(((1r,4r)-4-甲基环己基)氨基)苯基)乙磺酰胺(3.5g,产率:66%)。2-Bromo-N1-((1r,4r)-4-methylcyclohexyl)benzene-1,4-diamine (4.0 g, 14 mmol) was dissolved in dichloromethane (100 mL), then pyridine (3.3 g) , 42 mmol), ethanesulfonyl chloride (1.8 g, 14.0 mmol), and the mixture was stirred at room temperature for 18 hours. Water (300 mL) was added, the aqueous was extracted with methylene chloride (300 mL), EtOAcjjjjjjjjjjjj Purification by a gradient elution to give the compound N-(3-bromo-4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)ethanesulfonamide (3.5 g, yield: 66%).
1H NMR(400MHz,CDCl 3):δ7.36(d,J=2.4Hz,1H),7.09(dd,J=8.8,2.5Hz,1H),6.59(d,J=8.8Hz,1H),6.47(s,1H),4.24(br,1H),3.23–3.11(m,1H),3.05(q,J=7.2Hz,2H),2.13–2.05(m,2H),1.81–1.74(m,2H),1.42(dd,J=6.8,3.6Hz,1H),1.37(t,J=7.2Hz,3H),1.27–1.16(m,2H),1.12–1.00(m,2H),0.93(d,J=6.4Hz,3H)。 1 H NMR (400MHz, CDCl 3 ): δ7.36 (d, J = 2.4Hz, 1H), 7.09 (dd, J = 8.8,2.5Hz, 1H), 6.59 (d, J = 8.8Hz, 1H), 6.47(s,1H), 4.24(br,1H), 3.23–3.11(m,1H), 3.05(q,J=7.2Hz, 2H), 2.13–2.05(m,2H),1.81–1.74(m, 2H), 1.42 (dd, J = 6.8, 3.6 Hz, 1H), 1.37 (t, J = 7.2 Hz, 3H), 1.27 - 1.16 (m, 2H), 1.12 - 1.00 (m, 2H), 0.93 (d) , J = 6.4 Hz, 3H).
MS m/z(ESI):375.0,377.0[M+H] + MS m/z (ESI): 375.0, 377.0 [M+H] +
第四步:N-(3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)-4-(((1r,4r)-4-甲基环己基)氨基)苯基)乙磺酰胺的制备The fourth step: N-(3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4) -Methylcyclohexyl)amino)phenyl)ethanesulfonamide
Figure PCTCN2018073989-appb-000078
Figure PCTCN2018073989-appb-000078
以N-(3-溴-4-(((1r,4r)-4-甲基环己基)氨基)苯基)乙磺酰胺(200mg,0.5mmol)为反应原料,参考实施例8第四步,得到化合物N-(3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)-4-(((1r,4r)-4-甲基环己基)氨基)苯基)乙磺酰胺(180mg,产率:58%)。Taking N-(3-bromo-4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)ethanesulfonamide (200mg, 0.5mmol) as the starting material, refer to the fourth step of Example 8. , the compound N-(3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-) Methylcyclohexyl)amino)phenyl)ethanesulfonamide (180 mg, yield: 58%).
MS m/z(ESI):581.2[M+H] + MS m/z (ESI): 581.2 [M+H] +
第五步:N-(3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(((1r,4r)-4-甲基环己基)氨基)苯基)乙磺酰胺的制备Step 5: N-(3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl) Preparation of amino)phenyl)ethanesulfonamide
Figure PCTCN2018073989-appb-000079
Figure PCTCN2018073989-appb-000079
以N-(3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)-4-(((1r,4r)-4-甲基环己基)氨基)苯基)乙磺酰胺(180mg,0.3mmol)为反应原料,参考实施例8第五步,得到化合物N-(3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(((1r,4r)-4-甲基环己基)氨基)苯基)乙磺酰胺(120mg,产率:91%)。N-(3-(6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methyl) Cyclohexyl)amino)phenyl)ethanesulfonamide (180 mg, 0.3 mmol) was used as the starting material of the reaction, and the compound of N.sup. -b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)ethanesulfonamide (120 mg, yield: 91%).
MS m/z(ESI):427.2[M+H] + MS m/z (ESI): 427.2 [M+H] +
第六步:4-(5-(乙基磺酰氨基)-2-(((1r,4r)-4-甲基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 6: 4-(5-(Ethylsulfonylamino)-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[ Preparation of 2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000080
Figure PCTCN2018073989-appb-000080
以N-(3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(((1r,4r)-4-甲基环己基)氨基)苯基)乙磺酰胺(120mg,0.28mmol)为反应原料,参考实施例8第六步,得到化合物4-(5-(乙基磺酰氨基)-2-(((1r,4r)-4-甲基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(11.2mg,产率:9.0%)。N-(3-(6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(((1r,4r)-4-methylcyclohexyl)amino)benzene Ethyl sulfonamide (120 mg, 0.28 mmol) was used as the starting material of the reaction, and the compound was obtained in the sixth step of Example 8 to give the compound 4-(5-(ethylsulfonylamino)-2-((1r,4r)-4- Methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (11.2 mg, yield: 9.0%).
1H NMR(400MHz,CD 3OD):δ7.31(d,J=3.2Hz,1H),7.13–7.09(m,1H),7.08(s,1H),7.00(d,J=2.4Hz,1H),6.71(d,J=8.8Hz,1H),6.33(d,J=3.2Hz,1H),3.17–3.07(m,1H),2.94(q,J=7.2Hz,2H),2.60(s,3H),1.93–1.85(m,2H),1.64–1.54(m,2H),1.29–1.17(m,4H),1.02–0.83(m,4H),0.79(d,J=6.4Hz,3H)。 1 H NMR (400MHz, CD 3 OD): δ7.31 (d, J = 3.2Hz, 1H), 7.13-7.09 (m, 1H), 7.08 (s, 1H), 7.00 (d, J = 2.4Hz, 1H), 6.71 (d, J = 8.8 Hz, 1H), 6.33 (d, J = 3.2 Hz, 1H), 3.17 - 3.07 (m, 1H), 2.94 (q, J = 7.2 Hz, 2H), 2.60 ( s, 3H), 1.93–1.85 (m, 2H), 1.64–1.54 (m, 2H), 1.29–1.17 (m, 4H), 1.02–0.83 (m, 4H), 0.79 (d, J=6.4 Hz, 3H).
MS m/z(ESI):455.2[M+H] + MS m/z (ESI): 455.2 [M+H] +
实施例10Example 10
4-(2-(环己三烯并氧基)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(cyclohexanetrienoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000081
Figure PCTCN2018073989-appb-000081
第一步:(3-溴-4-氟苯基)(甲基)硫烷的制备First step: Preparation of (3-bromo-4-fluorophenyl)(methyl)sulfane
Figure PCTCN2018073989-appb-000082
Figure PCTCN2018073989-appb-000082
3-溴-4-氟苯胺(19g,0.1mol)和铜粉(0.96g,15mmol)溶于1,2-二甲基二硫烷(50mL),将反应体系加热至80℃。缓慢的滴入亚硝酸异戊酯(15g,0.15mmol)以保持反应的内部温度不高于90℃。滴加完毕反应在90℃下搅拌两小时。反应液蒸干,甲苯(250mL)和稀盐酸水溶液(250mL,1M)加入到反应体系中,分液,有机相用稀盐酸(1M,150mL),水(150mL),饱和食盐水(150mL)洗涤,有机相干燥过滤,滤液蒸干,残留物通过减压蒸馏,收集蒸汽温度50-60℃的馏分来得到的(3-溴-4-氟苯基)(乙基)硫烷(15g,淡黄色油状,产率68%)。3-Bromo-4-fluoroaniline (19 g, 0.1 mol) and copper powder (0.96 g, 15 mmol) were dissolved in 1,2-dimethyldisulfane (50 mL), and the reaction was heated to 80 °C. Isoamyl nitrite (15 g, 0.15 mmol) was slowly added dropwise to maintain the internal temperature of the reaction not higher than 90 °C. After the dropwise addition, the reaction was stirred at 90 ° C for two hours. The reaction mixture was evaporated to dryness. EtOAc (EtOAc) The organic phase is dried and filtered, the filtrate is evaporated to dryness, and the residue is subjected to distillation under reduced pressure to obtain (3-bromo-4-fluorophenyl)(ethyl)sulfane (15 g, light) obtained from a fraction of steam at 50-60 ° C. Yellow oil, yield 68%).
1H NMR(400MHz,CDCl 3):δ7.46–7.38(m,1H),7.21–7.12(m,1H),7.08–6.99(m,1H),2.46(s,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.46 - 7.38 (m, 1H), 7.21 - 7.12 (m, 1H), 7.08 - 6.99 (m, 1H), 2.46 (s, 3H).
第二步:2-溴-1-氟-4-(甲磺酰)苯的制备The second step: preparation of 2-bromo-1-fluoro-4-(methanesulfonyl)benzene
Figure PCTCN2018073989-appb-000083
Figure PCTCN2018073989-appb-000083
将间氯过氧苯甲酸(860mg,4.98mmol)加入到(3-溴-4-氟苯基)(甲基)硫烷(500mg,2.26mmol)的二氯甲烷(10mL)溶液中,室温反应6小时。除去溶剂后的粗品使用柱分离(石油醚:乙酸乙酯=5:1,V/V)得到2-溴-1-氟-4-(甲磺酰)苯(400mg,产率70%)。m-Chloroperoxybenzoic acid (860 mg, 4.98 mmol) was added to a solution of (3-bromo-4-fluorophenyl)(methyl)sulfane (500 mg, 2.26 mmol) in dichloromethane (10 mL) 6 hours. After the solvent was removed, the crude product was purified (jjjjjjjjjjj
1H NMR(400MHz,CDCl 3):δ8.19(dd,J=6.2Hz,2.3Hz,1H),7.91(m,1H),7.37–7.29(m,1H),3.08(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ8.19 (dd, J = 6.2Hz, 2.3Hz, 1H), 7.91 (m, 1H), 7.37-7.29 (m, 1H), 3.08 (s, 3H).
第三步:2-溴-1-(环己三烯并氧基)-4-(甲磺酰)苯的制备The third step: preparation of 2-bromo-1-(cyclohexanetrienoxy)-4-(methanesulfonyl)benzene
Figure PCTCN2018073989-appb-000084
Figure PCTCN2018073989-appb-000084
在氮气保护0℃下,将氢化钠(38mg,0.95mmol,60%)加入到2-溴-1-氟-4-(甲磺酰)苯(200mg,0.79mmol)和环己醇(95mg,0.95mmol)的N,N-二甲基甲酰胺(5mL)溶液中,室温反应30分钟,然后在45℃下反应3小时。反应液冷却后用水(5mL)淬灭,乙酸乙酯(25mL×2)萃取,有机相干燥蒸干。粗品柱分离(石油醚:乙酸乙酯=5:1,V/V)得到2-溴-1-(环己三烯并氧基)-4-(甲磺酰)苯(170mg,产率65%)。Sodium hydride (38 mg, 0.95 mmol, 60%) was added to 2-bromo-1-fluoro-4-(methylsulfonyl)benzene (200 mg, 0.79 mmol) and cyclohexanol (95 mg, 0.95 mmol) of a solution of N,N-dimethylformamide (5 mL) was allowed to react at room temperature for 30 minutes and then at 45 ° C for 3 hours. After the reaction mixture was cooled, the mixture was evaporated. Crude column separation (petroleum ether: ethyl acetate = 5:1, V/V) afforded 2-bromo-1-(cyclohexanetrienoxy)-4-(methylsulfonyl)benzene (170 mg, yield 65 %).
1H NMR(400MHz,CDCl 3):δ8.11(d,J=2.3Hz,1H),7.81(dd,J=8.7Hz,2.3 Hz,1H),6.99(d,J=8.7Hz,1H),4.53–4.44(m,1H),3.04(s,3H),2.00–1.89(m,2H),1.89–1.78(m,2H),1.78–1.65(m,2H),1.60–1.37(m,4H). 1 H NMR (400MHz, CDCl 3 ): δ8.11 (d, J = 2.3Hz, 1H), 7.81 (dd, J = 8.7Hz, 2.3 Hz, 1H), 6.99 (d, J = 8.7Hz, 1H) , 4.53–4.44 (m, 1H), 3.04 (s, 3H), 2.00–1.89 (m, 2H), 1.89–1.78 (m, 2H), 1.78–1.65 (m, 2H), 1.60–1.37 (m, 4H).
第四步:2-(2-(环己三烯并氧基)-5-(甲磺酰)苯基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环的制备The fourth step: 2-(2-(cyclohexanetrienoxy)-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxine Preparation of boron penta ring
Figure PCTCN2018073989-appb-000085
Figure PCTCN2018073989-appb-000085
将2-溴-1-(环己三烯并氧基)-4-(甲磺酰)苯(1g,3mmol),4,4,4',4',5,5,5',5'-八甲基-2,2'-联(1,3,2-二噁硼戊环)(2.29g,9mmol),乙酸钾(0.88g,9mmol),三(二亚苄基丙酮)二钯(137mg,0.15mmol),2-二环己基磷-2',4',6'-三异丙基联苯(143mg,0.3mmol)加入到1,4-二氧六环(20mL),反应液在氮气保护下85℃反应16小时。将反应液蒸干,粗品经柱分离(石油醚:乙酸乙酯=6:4,V/V)得到2-(2-(环己三烯并氧基)-5-(甲磺酰)苯基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(400mg粗品,60%纯度),直接用于下一步反应。2-Bromo-1-(cyclohexanetrienoxy)-4-(methanesulfonyl)benzene (1 g, 3 mmol), 4,4,4',4',5,5,5',5' - octamethyl-2,2'-linked (1,3,2-dioxaborolan) (2.29 g, 9 mmol), potassium acetate (0.88 g, 9 mmol), tris(dibenzylideneacetone) palladium (137 mg, 0.15 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (143 mg, 0.3 mmol) was added to 1,4-dioxane (20 mL). The solution was reacted at 85 ° C for 16 hours under a nitrogen atmosphere. The reaction mixture was evaporated to dryness, and then purified,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Base 4,4,5,5-tetramethyl-1,3,2-dioxaborolan (400 mg crude, 60% purity) was used directly in the next reaction.
第五步:4-(2-(环己三烯并氧基)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Step 5: Preparation of 4-(2-(cyclohexanetrienoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000086
Figure PCTCN2018073989-appb-000086
将2-(2-(环己三烯并氧基)-5-(甲磺酰)苯基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(380mg,0.6mmol,粗品),4-氯-6-甲基-1H-吡咯并[2,3-b]吡啶(100mg,0.6mmol),四三苯基膦钯(70mg,0.06mmol)和碳酸钾(248mg,3mol)加入到乙醇/甲苯/水(v/v/v=9:3:1,10mL)的混合溶剂中。反应液在氮气保护下120℃微波反应0.5小时,将反应液蒸干后使用制备板分离(石油醚:乙酸乙酯=1:1,V/V)得到4-(2-(环己三烯并氧基)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(75mg,产率33%)。2-(2-(Cyclohexatrienoxy)-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (380 mg, 0.6 mmol, crude), 4-chloro-6-methyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.6 mmol), tetratriphenylphosphine palladium (70 mg, 0.06 mmol) Potassium carbonate (248 mg, 3 mol) was added to a mixed solvent of ethanol/toluene/water (v/v/v = 9:3:1, 10 mL). The reaction solution was subjected to microwave reaction at 120 ° C for 0.5 hour under a nitrogen atmosphere, and the reaction liquid was evaporated to dryness and then separated using a preparative plate ( petroleum ether: ethyl acetate = 1:1, V/V) to obtain 4-(2-(cyclohexylenetriene). Andoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (75 mg, yield 33%).
MS m/z(ESI):385.1[M+H] + MS m/z (ESI): 385.1 [M+H] +
第六步:4-(2-(环己三烯并氧基)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 6: 4-(2-(Cyclohexatrienoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Preparation of oxide
Figure PCTCN2018073989-appb-000087
Figure PCTCN2018073989-appb-000087
将间氯过氧苯甲酸(65mg,0.29mmol,70%)加入到4-(2-(环己三烯并氧基)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(75mg,0.19mmol)的四氢呋喃(2mL)溶液中。室温反应0.5小时将溶剂蒸干,制备板分离(二氯甲烷:甲醇=15:1,V/V),得到4-(2-(环己三烯并氧基)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(6mg,产率7.7%)。Addition of m-chloroperoxybenzoic acid (65 mg, 0.29 mmol, 70%) to 4-(2-(cyclohexanetrienoxy)-5-(methylsulfonyl)phenyl)-6-methyl-1H - a solution of pyrrolo[2,3-b]pyridine (75 mg, 0.19 mmol) in tetrahydrofuran (2 mL). The solvent was evaporated to dryness at room temperature for 0.5 hour, and a plate was separated (dichloromethane:methanol = 15:1, V/V) to give 4-(2-(cyclohexanetrienoxy)-5-(methanesulfonyl) Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (6 mg, yield 7.7%).
1H NMR(400MHz,CDCl 3):δ12.33(br,1H),8.02(d,J=2.4Hz,1H),7.94(dd,J=8.8Hz,2.4Hz,1H),7.34(d,J=3.3Hz,1H),7.21–7.11(m,2H),6.43(d,J=3.3Hz,1H),4.53–4.40(m,1H),3.08(s,3H),2.77(s,3H),1.94–1.83(m,2H),1.68–1.56(m,2H),1.56–1.44(m,2H),1.43–1.28(m,4H). 1 H NMR (400MHz, CDCl 3 ): δ12.33 (br, 1H), 8.02 (d, J = 2.4Hz, 1H), 7.94 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.34 (d, J=3.3 Hz, 1H), 7.21–7.11 (m, 2H), 6.43 (d, J=3.3 Hz, 1H), 4.53–4.40 (m, 1H), 3.08 (s, 3H), 2.77 (s, 3H) ), 1.94–1.83 (m, 2H), 1.68–1.56 (m, 2H), 1.56–1.44 (m, 2H), 1.43–1.28 (m, 4H).
MS m/z(ESI):401.1[M+H] + MS m/z (ESI): 401.1 [M+H] +
实施例11Example 11
4-(2-((环丙基甲基)氨基)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备4-(2-((cyclopropylmethyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide preparation
Figure PCTCN2018073989-appb-000088
Figure PCTCN2018073989-appb-000088
第一步:2-溴-N-(环丙基甲基)-4-(甲磺酰)苯胺的制备First step: Preparation of 2-bromo-N-(cyclopropylmethyl)-4-(methylsulfonyl)aniline
Figure PCTCN2018073989-appb-000089
Figure PCTCN2018073989-appb-000089
将2-溴-1-氟-4-(甲磺酰)苯(700mg,2.77mmol)溶于1,4-二氧六环(15mL),室温下加环丙基甲胺(1.18g,16.67mmol),反应在微波下140℃搅拌一个小时,降温后将反应液浓缩,用乙酸乙酯(40mL)稀释,然后用水(20mL×2)和饱和食盐水(20mL)洗涤,并用无水硫酸钠干燥,浓缩后经柱层析(石油醚:乙酸乙酯=5:1,V/V)得到化合物2-溴-N-(环丙基甲基)-4-(甲磺酰)苯胺(680mg,产率81%)。2-Bromo-1-fluoro-4-(methylsulfonyl)benzene (700 mg, 2.77 mmol) was dissolved in 1,4-dioxane (15 mL) and cyclopropylmethylamine (1.18 g, 16.67) (mmol), the reaction was stirred at 140 ° C for one hour in the microwave. After cooling, the reaction mixture was concentrated, diluted with ethyl acetate (40 mL), then washed with water (20mL×2) and brine (20mL) After drying, concentration and column chromatography (petroleum ether: ethyl acetate = 5:1, V/V) afforded compound 2-bromo-N-(cyclopropylmethyl)-4-(methylsulfonyl)aniline (680 mg) , yield 81%).
第二步:N-(环丙基甲基)-4-(甲磺酰)-2-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯胺的制备Second step: N-(cyclopropylmethyl)-4-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -base) preparation of aniline
Figure PCTCN2018073989-appb-000090
Figure PCTCN2018073989-appb-000090
2-溴-N-(环丙基甲基)-4-(甲磺酰)苯胺(680.0mg,2.24mmol),联硼酸频那醇酯(1.71g,6.73mmol),三(二亚苄基丙酮)二钯(103mg,0.112mmol),醋酸钾(483mg,4.93mmol),2-二环己基磷-2,4,6-三异丙基联苯(107mg,0.224mmol)溶于1,4-二氧六环(10mL),在氮气保护下80℃搅拌反应8小时,将反应液旋干后加入水(20mL),然后用乙酸乙酯萃取(20mL×2),有机相合并后依次用水(40mL)和饱和食盐水(40mL)洗涤,并用无水硫酸钠干燥,浓缩后柱层析(洗脱剂:石油醚:乙酸乙酯=5:1,V/V)得到N-(环丙基甲基)-4-(甲磺酰)-2-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯胺(560.0mg,产率71%)。2-bromo-N-(cyclopropylmethyl)-4-(methylsulfonyl)aniline (680.0 mg, 2.24 mmol), dinacol borate (1.71 g, 6.73 mmol), tris(dibenzylidene) Acetone) dipalladium (103 mg, 0.112 mmol), potassium acetate (483 mg, 4.93 mmol), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (107 mg, 0.224 mmol) dissolved in 1,4 - Dioxane (10 mL), the reaction was stirred at 80 ° C for 8 hours under a nitrogen atmosphere. The reaction mixture was evaporated to dryness, then water (20mL), then ethyl acetate (20mL × 2), (40 mL) and saturated brine (40 mL), and dried over anhydrous sodium sulfate. Methyl)-4-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamine (560.0 mg, produced) The rate is 71%).
第三步:N-(环丙基甲基)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(甲磺酰)苯胺的制备Third step: Preparation of N-(cyclopropylmethyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methylsulfonyl)aniline
Figure PCTCN2018073989-appb-000091
Figure PCTCN2018073989-appb-000091
将N-(环丙基甲基)-4-(甲磺酰)-2-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)苯胺(200.0mg,0.57mmol),溶于1,4-二氧六环(4mL)和水(1mL)的混合溶剂中,然后加入三(二亚苄基丙酮)二钯(16mg,0.0171mmol),磷酸三钾(302mg,1.43mmol),1,3,5,7-四甲基-6-苯基-2,4,8-三氧杂-6-磷酰金刚烷(18.3mg,0.0627mmol),通氮气5分钟,在微波120℃下搅拌一个小时。降温后将反应液浓缩,用乙酸乙酯(40mL)稀释,然后用水(20mL×2)和饱和食盐水(20mL)洗涤,并用无水硫酸钠干燥,浓缩后用柱层析(二氯甲烷:甲醇=20:1)分离得到化合物N-(环丙基甲基)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(甲磺酰)苯胺(21mg,产率10%)。N-(cyclopropylmethyl)-4-(methylsulfonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Aniline (200.0 mg, 0.57 mmol), dissolved in a mixed solvent of 1,4-dioxane (4 mL) and water (1 mL), followed by tris(dibenzylideneacetone) dipalladium (16 mg, 0.0171 mmol) , tripotassium phosphate (302 mg, 1.43 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphoryladamantane (18.3 mg, 0.0627 mmol) The mixture was stirred with nitrogen for 5 minutes and stirred at 120 ° C for one hour. After the reaction mixture was cooled, the mixture was evaporated, evaporated, evaporated with with with with with with Methanol = 20:1) The compound N-(cyclopropylmethyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methane) was isolated. Acyl) aniline (21 mg, yield 10%).
MS m/z(ESI):356.1[M+H] +MS m/z (ESI): 356.1 [M+H] + .
第四步:4-(2-((环丙基甲基)氨基)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Fourth step: 4-(2-((cyclopropylmethyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 - Preparation of oxides
Figure PCTCN2018073989-appb-000092
Figure PCTCN2018073989-appb-000092
将N-(环丙基甲基)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(甲磺酰)苯胺(21.0mg,0.056mmol)溶于二氯甲烷(2mL),在冰浴冷却下加入间氯过氧苯甲酸(14mg,0.084mmol),反应液在室温下搅拌一个小时后用硫代硫酸钠的溶液(5mL)淬灭,然后加入二氯甲烷(15mL),然后用水(20mL×2)和饱和食盐水(20mL)洗涤,并用无水硫酸钠干燥,过滤浓缩后,用柱层析(二氯甲烷:甲醇=20:1)提纯得到化合物4-(2-((环丙基甲基)氨基)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(2.5mg,产率10%)。N-(cyclopropylmethyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methylsulfonyl)aniline (21.0 mg, 0.056 Methyl acetate (2 mL) was added, and m-chloroperoxybenzoic acid (14 mg, 0.084 mmol) was added, and the mixture was stirred at room temperature for one hour and then quenched with sodium thiosulfate solution (5 mL). After the addition, dichloromethane (15 mL) was added, and then washed with water (20 mL×2) and brine (20 mL) and dried over anhydrous sodium sulfate. :1) Purification to give the compound 4-(2-((cyclopropylmethyl)amino)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide (2.5 mg, yield 10%).
1H NMR(400MHz,CDCl 3):δ11.80(s,1H),8.05(s,1H),8.01(d,J=2.4Hz,1H),7.40(d,J=3.2Hz,1H),7.25–7.11(m,2H),6.40(d,J=3.4Hz,1H),3.86(d,J=6.4Hz,2H),3.73(s,3H),3.20(s,3H),1.24–1.31(m,1H),0.58–0.49(m,2H),0.31–0.24(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ11.80 (s, 1H), 8.05 (s, 1H), 8.01 (d, J = 2.4Hz, 1H), 7.40 (d, J = 3.2Hz, 1H), 7.25–7.11 (m, 2H), 6.40 (d, J = 3.4 Hz, 1H), 3.86 (d, J = 6.4 Hz, 2H), 3.73 (s, 3H), 3.20 (s, 3H), 1.24–1.31 (m, 1H), 0.58–0.49 (m, 2H), 0.31–0.24 (m, 2H).
MS m/z(ESI):372.1[M+H] +MS m/z (ESI): 3721. [M+H] + .
实施例12Example 12
4-(2-异丁氧基-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Preparation of 4-(2-isobutoxy-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000093
Figure PCTCN2018073989-appb-000093
第一步:2-溴-1-异丁氧基-4-(甲磺酰)苯的制备First step: Preparation of 2-bromo-1-isobutoxy-4-(methylsulfonyl)benzene
Figure PCTCN2018073989-appb-000094
Figure PCTCN2018073989-appb-000094
以2-甲基丙烷-1-醇代替环己醇为反应原料,参照实施例10第三步,得到化合物2-溴-1-异丁氧基-4-(甲磺酰)苯(1.01g,产率83%)。2-methylpropan-1-ol was used instead of cyclohexanol as the starting material. Referring to the third step of Example 10, the compound 2-bromo-1-isobutoxy-4-(methylsulfonyl)benzene (1.01 g) was obtained. , yield 83%).
第二步:2-(2-异丁氧基-5-(甲磺酰)苯基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环的制备Second step: Preparation of 2-(2-isobutoxy-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan
Figure PCTCN2018073989-appb-000095
Figure PCTCN2018073989-appb-000095
以2-溴-1-异丁氧基-4-(甲磺酰)苯为反应原料,参照实施例10第四步,得到2-(2-异丁氧基-5-(甲磺酰)苯基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环(900mg,产率78%)。2-Bromo-1-isobutoxy-4-(methylsulfonyl)benzene was used as the starting material, and the fourth step of Example 10 was carried out to obtain 2-(2-isobutoxy-5-(methanesulfonyl). Phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (900 mg, yield 78%).
第三步:4-(2-异丁氧基-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Third step: Preparation of 4-(2-isobutoxy-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000096
Figure PCTCN2018073989-appb-000096
以2-(2-异丁氧基-5-(甲磺酰)苯基)-4,4,5,5-四甲基-1,3,2-二噁硼戊环为反应原料,参照实施例10第五步,得到化合物4-(2-异丁氧基-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(45mg,产率23%)。Using 2-(2-isobutoxy-5-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan as the starting material, The fifth step of Example 10 gave the compound 4-(2-isobutoxy-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (45 mg, Yield 23%).
MS m/z(ESI):359.1[M+H] +MS m/z (ESI): 359.1 [M+H] + .
第四步:4-(2-异丁氧基-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Fourth step: Preparation of 4-(2-isobutoxy-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000097
Figure PCTCN2018073989-appb-000097
以4-(2-异丁氧基-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶为反应原料,参照实施例10第六步,得到化合物4-(2-异丁氧基-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(16.4mg,产率53%)。Taking 4-(2-isobutoxy-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine as the starting material, refer to the sixth step of Example 10. To give the compound 4-(2-isobutoxy-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (16.4 mg, Yield 53%).
1H NMR(400MHz,CDCl 3):δ11.83(s,1H),8.02(s,1H),8.00(d,J=2.4Hz,1H),7.43(d,J=3.2Hz,1H),7.23–7.14(m,2H),6.46(d,J=3.4Hz,1H),3.86(d,J=6.4Hz,2H),3.09(s,3H),2.78(s,3H),1.98(dt,J=13.3,6.6Hz,1H),0.88(d,J=6.7Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ11.83 (s, 1H), 8.02 (s, 1H), 8.00 (d, J = 2.4Hz, 1H), 7.43 (d, J = 3.2Hz, 1H), 7.23–7.14(m,2H), 6.46(d,J=3.4Hz,1H),3.86(d,J=6.4Hz,2H),3.09(s,3H),2.78(s,3H),1.98(dt , J = 13.3, 6.6 Hz, 1H), 0.88 (d, J = 6.7 Hz, 6H).
MS m/z(ESI):375.1[M+H] + MS m/z (ESI): 375.1 [M+H] +
实施例13Example 13
6-甲基-4-(2-((反式)-4-甲基环己基)氨基)-5-(甲磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(2-((trans)-4-methylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000098
Figure PCTCN2018073989-appb-000098
第一步:4-(2-氟-5-(甲磺酰)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶First step: 4-(2-Fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000099
Figure PCTCN2018073989-appb-000099
室温下,在三口烧瓶中加入2-溴-1-氟-4-(甲磺酰)苯(0.42g,1.66mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(0.62g,1.49mmol),碳酸钾(0.41g,2.98mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.12g,0.16mmol),二氧六环(16mL)和水(4mL),氮气置换三次后加热至90℃过夜。冷却至室温后用乙酸乙酯(20mL)稀释,硅藻土过滤,硅藻土用乙酸乙酯洗涤(20mL),滤液用食盐水(10mL×3)洗涤,无水硫酸钠干燥,过滤,旋干,粗产物用柱层析(石油醚:乙酸乙酯=3:1,V/V)分离,得到4-(2-氟-5-(甲磺酰)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(0.65g,白色固体,94%)。2-Bromo-1-fluoro-4-(methylsulfonyl)benzene (0.42 g, 1.66 mmol), 6-methyl-4-(4,4,5,5-tetramethyl) was added to a three-necked flask at room temperature. Base-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.62 g, 1.49 mmol), potassium carbonate (0.41 g) , 2.98 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.12 g, 0.16 mmol), dioxane (16 mL) and water (4 mL). After three times, it was heated to 90 ° C overnight. After cooling to room temperature, it was diluted with ethyl acetate (20 mL), EtOAc (EtOAc)EtOAc. The crude product was isolated by column chromatography (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc 1-Toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.65 g, white solid, 94%).
MS m/z(ESI):459.1[M+H] +. MS m/z (ESI): 459.1 [M+H] + .
第二步:4-(2-氟-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶Step 2: 4-(2-Fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000100
Figure PCTCN2018073989-appb-000100
室温下,在圆底烧瓶中加入4-(2-氟-5-(甲磺酰)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(0.53g,1.16mmol),然后用叔丁醇(15mL)将其溶解,室温搅拌,然后加入氢氧化钾水溶液(0.32g,5.79mmol,1mL水),加热至65℃过夜,冷却至室温后用旋蒸将大多数叔丁醇除去,残留物用乙酸乙酯(25mL)溶解,有机相用盐水洗涤(10mL×3),无水硫酸钠干燥,过滤,旋干得4-(2-氟-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(0.37g,白色固体),粗产物直接用于下一步反应。4-(2-Fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine was added to a round bottom flask at room temperature. (0.53 g, 1.16 mmol), then dissolved with t-butanol (15 mL), stirred at room temperature then aqueous potassium hydroxide (0.32 g, 5.79 mmol, 1 mL water), warmed to 65 ° C overnight, cooled to room temperature The residue was removed with EtOAc (25 mL). 5-(-Methanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (0.37 g, white solid).
MS m/z(ESI):305.1[M+H] +. MS m/z (ESI): 305.1 [M+H] + .
第三步:4-(2-氟-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物The third step: 4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000101
Figure PCTCN2018073989-appb-000101
冰浴下,将4-(2-氟-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(0.32g,1.05mmol)溶解于四氢呋喃(20mL)中,然后将间氯过氧苯甲酸(85%,0.21g,1.05mmol)加入到反应液中,反应结束后,反应液用乙酸乙酯稀释(20mL)后用饱和碳酸氢钠水溶液洗涤(10mL×3),然后用饱和食盐水(10mL)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用柱层析分离(二氯甲烷:甲醇=25:1,V/V),得到4-(2-氟-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.23g,淡黄色固体,产率68%)。4-(2-Fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (0.32 g, 1.05 mmol) was dissolved in tetrahydrofuran under ice bath (20 mL), then m-chloroperoxybenzoic acid (85%, 0.21 g, 1.05 mmol) was added to the reaction mixture. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (20 mL) Wash (10 mL × 3), then wash with saturated brine (10 mL), EtOAc (EtOAc) /V), 4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.23 g, light) Yellow solid, yield 68%).
MS m/z(ESI):321.1[M+H]+.MS m/z (ESI): 321.1 [M+H]+.
第四步:6-甲基-4-(2-((反式)-4-甲基环己基)氨基)-5-(甲磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物Fourth step: 6-methyl-4-(2-((trans)-4-methylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000102
Figure PCTCN2018073989-appb-000102
在10毫升微波管中加入4-(2-氟-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.050g,0.16mmol),反-4-甲基环己胺(0.5mL)和N-甲基吡咯烷酮(3mL),在油浴中加热至140℃,反应过夜。反应液冷却至室温后用乙酸乙酯(20mL)稀释,饱和食盐水洗涤(10mL×5),有机相用无水硫酸钠干燥,过滤,旋干,粗产物用反相制备色谱分离,得到6-甲基-4-(2-((反式)-4-甲基环己基)氨基)-5-(甲磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.020g,白色固体,产率31%)。Add 4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.050g) to a 10 ml microwave tube , 0.16 mmol), trans-4-methylcyclohexylamine (0.5 mL) and N-methylpyrrolidone (3 mL) were heated to 140 ° C in an oil bath and allowed to react overnight. The reaction mixture was cooled to room temperature, then diluted with ethyl acetate (20 mL). -Methyl-4-(2-((trans)-4-methylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7 - Oxide (0.020 g, white solid, yield 31%).
1H NMR(400MHz,CDCl 3):δ12.27(br,1H),7.80(dd,J=8.8Hz,2.4Hz,1H),7.70(d,J=2.0Hz,1H),7.38(d,J=3.2Hz,1H),7.08(s,1H),6.79(d,J=8.8Hz,1H),6.37(d,J=3.2Hz,1H),4.28(d,J=7.6Hz,1H),3.37-3.26(m,1H),3.05(s,3H),2.78(s,3H),2.11-1.93(m,2H),1.75-1.73(m,2H),1.38-1.26(m,1H),1.11-0.98(m,4H),0.90(d,J=6.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.27 (br, 1H), 7.80 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.70 (d, J = 2.0Hz, 1H), 7.38 (d, J = 3.2 Hz, 1H), 7.08 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 3.2 Hz, 1H), 4.28 (d, J = 7.6 Hz, 1H) , 3.37-3.26(m,1H), 3.05(s,3H), 2.78(s,3H),2.11-1.93(m,2H),1.75-1.73(m,2H),1.38-1.26(m,1H) , 1.11 - 0.98 (m, 4H), 0.90 (d, J = 6.4 Hz, 3H).
MS m/z(ESI):414.2[M+H] +. MS m/z (ESI): 414.2 [M+H] + .
实施例14Example 14
4-(2-((反式)-4-(叔丁基)环己基)氧代)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((trans)-4-(tert-butyl)cyclohexyl)oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000103
Figure PCTCN2018073989-appb-000103
第一步:4-(2-((反式)-4-(叔丁基)环己基)氧代)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物First step: 4-(2-((trans)-4-(tert-butyl)cyclohexyl)oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[ 2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000104
Figure PCTCN2018073989-appb-000104
室温下,将反-4-叔丁基环己醇(0.10g,0.66mmol)溶解于N,N-二甲基甲酰胺(3mL)中,然后将氢化钠(60%,0.037g,0.92mmol)加入到反应液中,室温搅拌半小时。然后将4-(2-氟-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.04g,0.13mmol)的N,N-二甲基甲酰胺(1mL)滴加到反应体系中,室温搅拌过夜后用乙酸乙酯(20mL)稀释,饱和食盐水(20mL)洗涤,有机相用无水硫酸钠干燥,过滤后旋干,粗产物用反相制备色谱分离得到4-(2-((反式)-4-(叔丁基)环己基)氧代)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.030g,白色固体,产率53%)。Trans-4-tert-butylcyclohexanol (0.10 g, 0.66 mmol) was dissolved in N,N-dimethylformamide (3 mL), then sodium hydride (60%, EtOAc, The reaction solution was stirred at room temperature for half an hour. 4-(2-Fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.04 g, 0.13 mmol) N,N-dimethylformamide (1 mL) was added dropwise to the reaction mixture, and the mixture was stirred with EtOAc EtOAc (EtOAc) After spin-drying, the crude product was isolated by reverse phase preparative chromatography to give 4-(2-((trans)-4-(tert-butyl)cyclohexyl)oxy)-5-(methylsulfonyl)phenyl)-6 Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.030 g, white solid, yield 53%).
MS m/z(ESI):457.2[M+H] +. MS m / z (ESI): 457.2 [M + H] +.
1H NMR(400MHz,CDCl 3):δ11.96(br,1H),8.00(d,J=2.4Hz,1H),7.94(dd,J 8.8Hz,2.4Hz 1H),7.35(d,J=3.2Hz,1H),7.16(d,J=8.8Hz,1H),7.13(s,1H),6.38(d,J=3.2Hz,1H),4.36-4.24(m,1H),3.08(s,3H),2.77(s,3H),2.15-2.12(m,2H),1.85-1.82(m,2H),1.34-1.25(m,2H),1.17-0.97(m,3H),0.85(s,9H). 1 H NMR (400MHz, CDCl 3 ): δ11.96 (br, 1H), 8.00 (d, J = 2.4Hz, 1H), 7.94 (dd, J 8.8Hz, 2.4Hz 1H), 7.35 (d, J = 3.2 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 6.38 (d, J = 3.2 Hz, 1H), 4.36-4.24 (m, 1H), 3.08 (s, 3H), 2.77 (s, 3H), 2.15-2.12 (m, 2H), 1.85-1.82 (m, 2H), 1.34-1.25 (m, 2H), 1.17-0.97 (m, 3H), 0.85 (s, 9H).
实施例15Example 15
6-甲基-4-(2-(((反式)-4-甲基环己基)氧代)-5-(甲磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(2-(((trans)-4-methylcyclohexyl)oxy)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b] Pyridine-7-oxide
Figure PCTCN2018073989-appb-000105
Figure PCTCN2018073989-appb-000105
按照实施例14的实验步骤,以反-4-甲基环己醇代替反-4-叔丁基环己醇为原料,得到4-(2-((反式)-4-甲基环己基)氧代)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.035g,白色固体,产率49%)。According to the experimental procedure of Example 14, trans-4-methylcyclohexanol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((trans)-4-methylcyclohexyl)oxy). -5-(Methanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.035 g, white solid, yield 49%).
MS m/z(ESI):415.2[M+H] +. MS m/z (ESI): 415.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.70(br,1H),7.99-7.94(m,2H),7.41(d,J=3.2Hz,1H),7.18-7.16(m,2H),6.46(d,J=3.2Hz,1H),4.39-4.28(m,1H),3.09(s,3H),2.79(s,3H),2.09-2.06(m,2H),1.78-1.75(m,2H),1.38-1.28(m,3H),1.09-1.00(m, 2H),0.91(d,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.70 (br, 1H), 7.99-7.94 (m, 2H), 7.41 (d, J = 3.2Hz, 1H), 7.18-7.16 (m, 2H), 6.46 (d, J=3.2 Hz, 1H), 4.39-4.28 (m, 1H), 3.09 (s, 3H), 2.79 (s, 3H), 2.09-2.06 (m, 2H), 1.78-1.75 (m, 2H) ), 1.38-1.28 (m, 3H), 1.09-1.00 (m, 2H), 0.91 (d, J = 7.2 Hz, 3H).
实施例16Example 16
4-(2-((反式)-4-乙基环己基)氧代)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((trans)-4-ethylcyclohexyl)oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide
Figure PCTCN2018073989-appb-000106
Figure PCTCN2018073989-appb-000106
按照实施例14的实验步骤,以反-4-乙基环己醇代替反-4-叔丁基环己醇为原料,得到4-(2-((反式)-4-乙基环己基)氧代)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.023g,白色固体,产率58%)。According to the experimental procedure of Example 14, trans-4-ethylcyclohexanol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((trans)-4-ethylcyclohexyl)oxy). -5-(Methanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.023 g, white solid, yield 58%).
MS m/z(ESI):429.2[M+H]+.MS m/z (ESI): 429.2 [M+H]+.
1HNMR(400MHz,CDCl 3):δ11.86(br,1H),7.99(s,1H),7.94(d,J=8.8Hz,1H),7.35(d,J=8.8Hz,1H),7.17-7.13(m,2H),6.42(d,J=3.2Hz,1H),4.35-4.27(m,1H),3.08(s,3H),2.76(s,3H),2.10-2.07(m,2H),1.84-1.81(m,2H),1.36-1.08(m,5H),1.04-0.96(m,2H),0.87(d,J=7.2Hz,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 11.86 (br, 1H), 7.99 (s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.8 Hz, 1H), 7.17 -7.13 (m, 2H), 6.42 (d, J = 3.2 Hz, 1H), 4.35-4.27 (m, 1H), 3.08 (s, 3H), 2.76 (s, 3H), 2.10-2.07 (m, 2H) ), 1.84-1.81 (m, 2H), 1.36-1.08 (m, 5H), 1.04-0.96 (m, 2H), 0.87 (d, J = 7.2 Hz, 3H).
实施例17Example 17
4-(2-((反式)-4-异丙基环己基)氧代)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((trans)-4-isopropylcyclohexyl)oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Pyridine-7-oxide
Figure PCTCN2018073989-appb-000107
Figure PCTCN2018073989-appb-000107
按照实施例14的实验步骤,以反-4-异丙基环己醇代替反-4-叔丁基环己醇为原料,得到4-(2-((反式)-4-异丙基环己基)氧代)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.018g,产率44%)。According to the experimental procedure of Example 14, trans-4-isopropylcyclohexanol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((trans))-4-isopropylcyclohexyl. Oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.018 g, yield 44%).
MS m/z(ESI):443.2[M+H] +. MS m/z (ESI): 443.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.96(br,1H),8.00(d,J=2.0Hz,1H),7.96(dd,J8.8Hz,2.0Hz 1H),7.36(d,J=3.2Hz,1H),7.17-7.14(m,2H),6.43(d,J=3.2Hz,1H),4.34-4.26(m,1H),3.09(s,3H),2.77(s,3H),2.13-2.10(m,2H),1.80-1.77(m,2H),1.49-1.39(m,1H),1.35-1.25(m,2H),1.15-1.06(m,3H),0.86(d,J=6.8Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ11.96 (br, 1H), 8.00 (d, J = 2.0Hz, 1H), 7.96 (dd, J8.8Hz, 2.0Hz 1H), 7.36 (d, J = 3.2 Hz, 1H), 7.17-7.14 (m, 2H), 6.43 (d, J = 3.2 Hz, 1H), 4.34 - 4.26 (m, 1H), 3.09 (s, 3H), 2.77 (s, 3H), 2.13-2.10(m,2H),1.80-1.77(m,2H), 1.49-1.39(m,1H),1.35-1.25(m,2H),1.15-1.06(m,3H),0.86(d,J =6.8Hz, 6H).
实施例18Example 18
4-(2-(((1S,2R,5S)-2-异丙基-5-甲基环己基)氧代)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H- Pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000108
Figure PCTCN2018073989-appb-000108
按照实施例14的实验步骤,以L-薄荷醇代替反-4-叔丁基环己醇为原料,得到4-(2-(((1S,2R,5S)-2-异丙基-5-甲基环己基)氧代)-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.020g,白色固体,产率47%)。According to the experimental procedure of Example 14, L-menthol was used instead of trans-4-tert-butylcyclohexanol to obtain 4-(2-((1(1,2R,5S)-2-isopropyl-5-) Cyclohexyl)oxo)-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.020 g, white solid, yield 47%).
MS m/z(ESI):457.2[M+H] +. MS m/z (ESI): 457.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.59(br,1H),8.00(d,J=2.4Hz,1H),7.94(dd,J=8.8Hz,2.4Hz,1H),7.30(d,J=3.6Hz,1H),7.16(d,J=8.4Hz,1H),7.12(s,1H),6.40(d,J=3.6Hz,1H),4.25-4.19(m,1H),3.09(s,3H),2.75(s,3H),2.18-2.15(m,1H),1.93-1.85(m,1H),1.68-1.60(m,2H),1.56-1.43(m,1H),1.36-1.29(m,1H),1.12-0.85(m,6H),0.77(d,J=7.2Hz,3H),0.66(d,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.59 (br, 1H), 8.00 (d, J = 2.4Hz, 1H), 7.94 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.40 (d, J = 3.6 Hz, 1H), 4.25 - 4.19 (m, 1H), 3.09 ( s, 3H), 2.75 (s, 3H), 2.18-2.15 (m, 1H), 1.93-1.85 (m, 1H), 1.68-1.60 (m, 2H), 1.56-1.43 (m, 1H), 1.36- 1.29 (m, 1H), 1.12 - 0.85 (m, 6H), 0.77 (d, J = 7.2 Hz, 3H), 0.66 (d, J = 7.2 Hz, 3H).
实施例19Example 19
6-甲基-4-(2-((反式)-4-乙基环己基)氨基)-5-(甲磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000109
Figure PCTCN2018073989-appb-000109
第一步:N-(4-乙基环己基)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(甲磺酰)苯胺First step: N-(4-ethylcyclohexyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methylsulfonyl)aniline
Figure PCTCN2018073989-appb-000110
Figure PCTCN2018073989-appb-000110
在10毫升微波管中加入4-(2-氟-5-(甲磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.040g,0.125mmol),4-乙基环己胺(0.3mL)和N-甲基吡咯烷酮(3mL),在油浴中加热至140℃,反应过夜,冷却至室温。反应液用乙酸乙酯(20mL)稀释,盐水(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,得粗产物N-(4-乙基环己基)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(甲磺酰)苯胺 (0.060g,黄色油状物)直接用于下一步反应。Add 4-(2-fluoro-5-(methylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.040g) to a 10 ml microwave tube , 0.125 mmol), 4-ethylcyclohexylamine (0.3 mL) and N-methylpyrrolidone (3 mL), heated to 140 ° C in an oil bath, and allowed to react overnight and cooled to room temperature. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc (EtOAc) 6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methylsulfonyl)aniline (0.060 g, yellow oil) was used directly for next step.
MS m/z(ESI):412.2[M+H] +. MS m/z (ESI): 412.2 [M+H] + .
第二步:6-甲基-4-(2-((反式)-4-乙基环己基)氨基)-5-(甲磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物Second step: 6-methyl-4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000111
Figure PCTCN2018073989-appb-000111
将粗产物N-(4-乙基环己基)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(甲磺酰)苯胺(0.060g,黄色油状物)溶解于二氯甲烷中(10mL),然后将间氯过氧苯甲酸(85%,0.051g,0.25mmol)加入到反应液中,室温搅拌。反应结束后,反应液用二氯甲烷(40mL)稀释,饱和碳酸氢钠水溶液(25mL)洗涤,饱和食盐水(25mL)洗涤,无水硫酸钠干燥,过滤,旋干,粗产物用反相制备色谱分离得到6-甲基-4-(2-((反式)-4-乙基环己基)氨基)-5-(甲磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.012g,白色固体,产率19%)。The crude product N-(4-ethylcyclohexyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(methylsulfonyl)aniline (0.060) g, yellow oil) was dissolved in dichloromethane (10 mL), then m-chloroperoxybenzoic acid (85%, 0.051 g, 0.25 mmol) was added to the reaction mixture and stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with methylene chloride (40 mL), EtOAc. Chromatography to give 6-methyl-4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b Pyridine-7-oxide (0.012 g, white solid, yield 19%).
MS m/z(ESI):428.2[M+H] +. MS m/z (ESI): 428.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ12.2(br,1H),7.80(dd,J=8.8Hz,2.0Hz,1H),7.70(d,J=2.0Hz 1H),7.39(d,J=3.2Hz,1H),7.08(s,1H),6.79(d,J=8.8Hz,1H),6.37(d,J=3.2Hz,1H),4.30(d,J=7.2Hz,1H),3.39-3.26(br,1H),3.05(s,3H),2.78(s,3H),2.16-1.95(m,2H),1.82-1.78(m,2H),1.27-1.20(m,2H),1.13-0.94(m,5H),0.87(t,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.2 (br, 1H), 7.80 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.70 (d, J = 2.0Hz 1H), 7.39 (d, J =3.2 Hz, 1H), 7.08 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 3.2 Hz, 1H), 4.30 (d, J = 7.2 Hz, 1H), 3.39-3.26(br,1H), 3.05(s,3H), 2.78(s,3H),2.16-1.95(m,2H),1.82-1.78(m,2H),1.27-1.20(m,2H), 1.13-0.94 (m, 5H), 0.87 (t, J = 7.2 Hz, 3H).
实施例20Example 20
6-甲基-4-(2-((顺式)-4-乙基环己基)氨基)-5-(甲磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(2-((cis)-4-ethylcyclohexyl)amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000112
Figure PCTCN2018073989-appb-000112
按照实施例19的实验步骤,反相制备色谱分离同时得到6-甲基-4-(2-((顺式)-4-乙基环己基)氨基)-5-(甲磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.015g,白色固体,产率28%)。According to the experimental procedure of Example 19, reverse phase preparative chromatography was carried out to give 6-methyl-4-(2-((cis)-4-ethylcyclohexyl)amino)-5-(methylsulfonyl)phenyl. -1H-pyrrolo[2,3-b]pyridine-7-oxide (0.015 g, white solid, yield 28%).
MS m/z(ESI):428.2[M+H] +. MS m/z (ESI): 428.2 [M+H] + .
1HNMR(400MHz,CDCl 3):δ12.21(br,1H),7.80(d,J=8.8Hz,1H),7.72(s, 1H),7.39(d,J=3.2Hz,1H),7.08(s,1H),6.79(d,J=8.8Hz,1H),6.44(d,J=3.2Hz,1H),4.54(d,J=6.4Hz,1H),3.66(br,1H),3.05(s,3H),2.79(s,3H),1.74-1.48(m,6H),1.25-1.12(m,3H),1.02-0.86(m,2H),0.82(t,J=7.2Hz,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 12.21. (br, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.72 (s, 1H), 7.39 (d, J = 3.2 Hz, 1H), 7.08 (s, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 3.2 Hz, 1H), 4.54 (d, J = 6.4 Hz, 1H), 3.66 (br, 1H), 3.05 (s, 3H), 2.79 (s, 3H), 1.74-1.48 (m, 6H), 1.25-1.12 (m, 3H), 1.02-0.86 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H) ).
实施例21Example 21
6-甲基-4-(5-(甲磺酰)-2-(((反式)-4-丙基环己基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(5-(methylsulfonyl)-2-(((trans)-4-propylcyclohexyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine -7-oxide
Figure PCTCN2018073989-appb-000113
Figure PCTCN2018073989-appb-000113
按照实施例19的实验步骤,以4-丙基环己胺代替4-乙基环己胺为原料,得到6-甲基-4-(2-((反式)-4-丙基环己基)氨基)-5-(甲磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.010g,淡黄色固体,产率18%)。Following the experimental procedure of Example 19, 4-propylcyclohexylamine was used instead of 4-ethylcyclohexylamine to give 6-methyl-4-(2-((trans)-4-propylcyclohexyl). Amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.010 g, pale yellow solid, yield 18%).
MS m/z(ESI):442.2[M+H] +. MS m/z (ESI): 442.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ12.14(br,1H),7.80(dd,J=8.8Hz,2.0Hz,1H),7.71(d,J=2.0Hz,1H),7.39(d,J=3.2Hz,1H),7.08(s,1H),6.80(d,J=8.8Hz,1H),6.38(d,J=3.2Hz,1H),4.30(d,J=7.6Hz,1H),3.32(br,1H),3.05(s,3H),2.78(s,3H),2.02(br,2H),1.80-1.78(m,2H),1.36-1.24(m,2H),1.20-1.16(m,3H),1.04-1.00(m,4H),0.87(t,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.14 (br, 1H), 7.80 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.71 (d, J = 2.0Hz, 1H), 7.39 (d, J = 3.2 Hz, 1H), 7.08 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.38 (d, J = 3.2 Hz, 1H), 4.30 (d, J = 7.6 Hz, 1H) , 3.32(br,1H), 3.05(s,3H), 2.78(s,3H),2.02(br,2H),1.80-1.78(m,2H),1.36-1.24(m,2H),1.20-1.16 (m, 3H), 1.04-1.00 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H).
实施例22Example 22
6-甲基-4-(5-(甲磺酰)-2-((顺式)-4-丙基环己基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(5-(methylsulfonyl)-2-((cis)-4-propylcyclohexyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000114
Figure PCTCN2018073989-appb-000114
按照实施例19的实验步骤,以4-丙基环己胺代替4-乙基环己胺为原料,得到6-甲基-4-(2-((顺式)-4-丙基环己基)氨基)-5-(甲磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.010g,淡黄色固体,产率18%)。Following the experimental procedure of Example 19, 4-propylcyclohexylamine was used instead of 4-ethylcyclohexylamine to give 6-methyl-4-(2-((cis))-4-propylcyclohexyl. Amino)-5-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.010 g, pale yellow solid, yield 18%).
MS m/z(ESI):442.2[M+H] +. MS m / z (ESI): 442.2 [M + H] +.
1H NMR(400MHz,CDCl 3):δ11.62(br,1H),7.80(dd,J=8.8Hz,2.0Hz,1H),7.73(d,J=2.0Hz,1H),7.33(d,J=3.2Hz,1H),7.08(s,1H),6.76(d,J=8.8 Hz,1H),6.42(d,J=3.2Hz,1H),4.57(d,J=6.8Hz,1H),3.65(br,1H),3.05(s,3H),2.77(s,3H),1.73-1.61(m,4H),1.55-1.49(m,2H),1.38-1.27(m,1H),1.26-1.20(m,2H),1.13-1.07(m,2H),0.95-0.88(m,2H),0.86(t,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.62 (br, 1H), 7.80 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.73 (d, J = 2.0Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.08 (s, 1H), 6.76 (d, J = 8.8 Hz, 1H), 6.42 (d, J = 3.2 Hz, 1H), 4.57 (d, J = 6.8 Hz, 1H) , 3.65 (br, 1H), 3.05 (s, 3H), 2.77 (s, 3H), 1.73-1.61 (m, 4H), 1.55-1.49 (m, 2H), 1.38-1.27 (m, 1H), 1.26 -1.20 (m, 2H), 1.13-1.07 (m, 2H), 0.95-0.88 (m, 2H), 0.86 (t, J = 7.2 Hz, 3H).
实施例23Example 23
4-(5-((2-氰基丙烷-2-基)磺酰)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-((2-Cyanopropan-2-yl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000115
Figure PCTCN2018073989-appb-000115
第一步:1,2-二(3-溴-4-氟苯基)二硫烷的制备.The first step: the preparation of 1,2-bis(3-bromo-4-fluorophenyl)disulfane.
Figure PCTCN2018073989-appb-000116
Figure PCTCN2018073989-appb-000116
3L三口瓶中依次加入3-溴-4-氟苯胺(60g,315.6mmol),乙腈(600mL),水(600mL),浓盐酸(300mL)。冰浴冷却至0-5℃,滴加亚硝酸钠(23.4g,316mmol)的水(300mL)溶液,维持体系温度在0-5℃。反应1小时后加入尿素(3.6g,60mmol)淬灭多余的亚硝酸钠,搅拌10分钟。1L的三口瓶中依次加入九水硫化钠(100.8g,420mmol),硫磺粉(13.2g,420mmol),NaOH(17.4g,432mmol),水(300mL)。油浴加热至75℃反应1小时至溶液变澄清。将澄清溶液冷却至室温滴加到上述反应液中,并维持体系温度为0-5℃。滴加完毕后,反应液用乙酸乙酯(1L×2)萃取,过滤,无水硫酸钠干燥,旋干得到粗品1,2-二(3-溴-4-氟苯基)二硫烷(42g,黄色油状物,产率65%)。3-Bromo-4-fluoroaniline (60 g, 315.6 mmol), acetonitrile (600 mL), water (600 mL), and concentrated hydrochloric acid (300 mL). The mixture was cooled to 0-5 ° C in an ice bath, and a solution of sodium nitrite (23.4 g, 316 mmol) in water (300 mL) was added dropwise, maintaining the system temperature at 0-5 °C. After 1 hour of reaction, urea (3.6 g, 60 mmol) was added to quench excess sodium nitrite and stirred for 10 minutes. Sodium sulfide nonahydrate (100.8 g, 420 mmol), sulfur powder (13.2 g, 420 mmol), NaOH (17.4 g, 432 mmol), water (300 mL) were sequentially added to a 1 L three-necked flask. The oil bath was heated to 75 ° C for 1 hour until the solution became clear. The clear solution was cooled to room temperature and added dropwise to the above reaction liquid, and the temperature of the system was maintained at 0 to 5 °C. After completion of the dropwise addition, the reaction mixture was extracted with ethyl acetate (1L×2), filtered, dried over anhydrous sodium sulfate and evaporated to give the crude (1,2-bis(3-bromo-4-fluorophenyl)disulfane ( 42 g, yellow oil, yield 65%).
第二步:3-溴-4-氟苯硫醇的制备The second step: the preparation of 3-bromo-4-fluorobenzenethiol
Figure PCTCN2018073989-appb-000117
Figure PCTCN2018073989-appb-000117
3L三口瓶中依次加入1,2-二(3-溴-4-氟苯基)二硫烷(42g,101.9mmol),甲醇(300mL),四氢呋喃(1L),氢氧化钠(10.3g,257.5mmol)的水(300mL)溶液。室温下分五批加入硼氢化钠(11.1g,293.6mmol)。反应1小时后浓缩,加入氢氧化钠(35g,875.0mmol)的水(300mL)溶液,用甲基叔丁基醚(500mL×2)萃取移除杂质。水相滴加到盐酸水溶液(3M,800mL)中,并维持体系温度为0-5℃。反应液用甲基叔丁基醚(500mL×3)萃取,无水硫酸钠干燥,旋 干得到3-溴-4-氟苯硫醇(16g,黄色油状物,产率38%)。1,2-bis(3-bromo-4-fluorophenyl)disulfane (42 g, 101.9 mmol), methanol (300 mL), tetrahydrofuran (1 L), sodium hydroxide (10.3 g, 257.5) were sequentially added to a 3L three-necked flask. A solution of mmol (300 mL) of water. Sodium borohydride (11.1 g, 293.6 mmol) was added in five portions at room temperature. After 1 hour of reaction, it was concentrated, and a solution of sodium hydroxide (35 g, 875.0 mmol) in water (300 mL) was added, and extracted with methyl tert-butyl ether (500 mL × 2) to remove impurities. The aqueous phase was added dropwise to aqueous hydrochloric acid (3M, 800 mL) and the system temperature was maintained from 0 to 5 °C. The reaction mixture was extracted with EtOAc (EtOAc)EtOAc.
1H NMR(400MHz,CDCl 3):δ7.50(dd,J=6.4Hz,2.4Hz,1H),7.23–7.16(m,1H),7.00(t,J=8.4Hz,1H),3.48(s,1H). 1 H NMR (400MHz, CDCl 3 ): δ7.50 (dd, J = 6.4Hz, 2.4Hz, 1H), 7.23-7.16 (m, 1H), 7.00 (t, J = 8.4Hz, 1H), 3.48 ( s, 1H).
第三步:2-((3-溴-4-氟苯基)硫代)乙酰腈The third step: 2-((3-bromo-4-fluorophenyl)thio)acetonitrile
Figure PCTCN2018073989-appb-000118
Figure PCTCN2018073989-appb-000118
冰浴下,将溴乙腈(1.74g,14.5mmol)溶解于N,N-二甲基甲酰胺(10mL)中,然后将4-氟-3-溴苯硫酚(1.50g,7.25mmol)的N,N-二甲基甲酰胺(5mL)溶液加入到反应液中,最后加入碳酸铯(4.73g,14.5mmol),室温反应。反应结束后,反应液用乙酸乙酯(30mL)稀释,饱和食盐水(10mL×3)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用制备板分离(石油醚:乙酸乙酯=3:1)得到2-((3-溴-4-氟苯基)硫代)乙酰腈(1.0g,黄色油状物,产率:56%)。Bromine acetonitrile (1.74 g, 14.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), then 4-fluoro-3-bromothiophenol (1.50 g, 7.25 mmol) A solution of N,N-dimethylformamide (5 mL) was added to the reaction mixture, and finally cesium carbonate (4.73 g, 14.5 mmol) was added and reacted at room temperature. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), brine, brine, evaporated, evaporated. Ethyl ester = 3:1) 2-((3-bromo-4-fluorophenyl)thio)acetonitrile (1.0 g, yellow oil, yield: 56%).
1H NMR(400MHz,CDCl 3):δ7.81(dd,J=6.4Hz,2.4Hz,1H),7.58-7.54(m,1H),7.18(t,J=8.4Hz,1H),3.57(s,2H). 1 H NMR (400MHz, CDCl 3 ): δ7.81 (dd, J = 6.4Hz, 2.4Hz, 1H), 7.58-7.54 (m, 1H), 7.18 (t, J = 8.4Hz, 1H), 3.57 ( s, 2H).
第四步:2-((3-溴-4-氟苯基)磺酰)乙酰腈Step 4: 2-((3-Bromo-4-fluorophenyl)sulfonyl)acetonitrile
Figure PCTCN2018073989-appb-000119
Figure PCTCN2018073989-appb-000119
冰浴下,将2-((3-溴-4-氟苯基)硫代)乙酰腈(0.50g,2.03mmol)溶解于二氯甲烷(10mL)中,然后将间氯过氧苯甲酸(0.93g,4.06mmol)加入到反应体系中,室温搅拌过夜。反应结束后,反应体系用二氯甲烷(25mL)稀释,饱和碳酸氢钠水溶液(10mL)洗涤,盐水(10mL)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用柱层析分离得到2-((3-溴-4-氟苯基)磺酰)乙酰腈(0.30g,无色油状物,产率:53%)。2-((3-Bromo-4-fluorophenyl)thio)acetonitrile (0.50 g, 2.03 mmol) was dissolved in dichloromethane (10 mL) and then m-chloroperoxybenzoic acid ( 0.93 g, 4.06 mmol) was added to the reaction system and stirred at room temperature overnight. After the reaction, the reaction mixture was diluted with methylene chloride (25 mL), EtOAc (EtOAc) Isolated to give 2-((3-bromo-4-fluorophenyl)sulfonyl)acetonitrile (0.30 g,yield:yield: 53%).
第五步:2-((3-溴-4-(2,4-二氟苯氧基)苯基)磺酰)乙酰腈Step 5: 2-((3-Bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)acetonitrile
Figure PCTCN2018073989-appb-000120
Figure PCTCN2018073989-appb-000120
室温下,将2-((3-溴-4-氟苯基)磺酰)乙酰腈(0.29g,1.04mmol),2,4-二氟苯酚(0.41g,3.12mmol)以及碳酸钠(0.33g,3.12mmol)溶解于二甲基亚砜(5mL),氮气 保护,加热至90℃,反应两小时。反应结束后,冷却至室温,反应液用乙酸乙酯(35mL)稀释,饱和食盐水(15mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用柱层析(石油醚:乙酸乙酯=3:1,V/V)分离得到2-((3-溴-4-(2,4-二氟苯氧基)苯基)磺酰)乙酰腈(0.25g,白色固体,产率:62%)。2-((3-Bromo-4-fluorophenyl)sulfonyl)acetonitrile (0.29 g, 1.04 mmol), 2,4-difluorophenol (0.41 g, 3.12 mmol) and sodium carbonate (0.33) g, 3.12 mmol) was dissolved in dimethyl sulfoxide (5 mL), protected with nitrogen and heated to 90 ° C for two hours. After completion of the reaction, the mixture was cooled to room temperature. The mixture was diluted with ethyl acetate (35 mL). Petroleum ether: ethyl acetate = 3:1, V/V) 2-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)acetonitrile (0.25 g, White solid, yield: 62%).
MS m/z(ESI):386.0,388.0[M-H] -. MS m/z (ESI): 386.0, 388.0 [MH] - .
第六步:2-((3-溴-4-(2,4-二氟苯氧基)苯基)磺酰)-2-甲基丙腈Step 6: 2-((3-Bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)-2-methylpropanenitrile
Figure PCTCN2018073989-appb-000121
Figure PCTCN2018073989-appb-000121
室温下,将2-((3-溴-4-(2,4-二氟苯氧基)苯基)磺酰)乙酰腈(0.10g,0.26mmol)和碳酸铯(0.17g,0.52mmol)溶解于四氢呋喃(10mL)中,然后将碘甲烷(0.5mL)滴加到反应液中,室温反应三小时。反应结束后,反应液用乙酸乙酯(25mL)稀释,饱和食盐水(15mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,得粗产物2-((3-溴-4-(2,4-二氟苯氧基)苯基)磺酰)-2-甲基丙腈(0.10g,白色固体)直接用于下一步反应。2-((3-Bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)acetonitrile (0.10 g, 0.26 mmol) and cesium carbonate (0.17 g, 0.52 mmol) It was dissolved in tetrahydrofuran (10 mL), and then methyl iodide (0.5 mL) was added dropwise to the reaction mixture, and the mixture was reacted at room temperature for three hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (25 mL), EtOAc (EtOAc) 4-(2,4-Difluorophenoxy)phenyl)sulfonyl)-2-methylpropanenitrile (0.10 g, white solid) was used directly for next step.
MS m/z(ESI):416.0,418.0[M+H] +. MS m/z (ESI): 416.0, 418.0 [M+H] + .
第七步:2-((4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)-2-甲基丙腈Step 7: 2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 -yl)phenyl)sulfonyl)-2-methylpropionitrile
Figure PCTCN2018073989-appb-000122
Figure PCTCN2018073989-appb-000122
室温下,将2-((3-溴-4-(2,4-二氟苯氧基)苯基)磺酰)-2-甲基丙腈(0.10g,0.24mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(0.13g,0.24mmol),碳酸钾(0.066g,0.48mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.018g,0.024mmol)溶解于二氧六环(4mL)和水(1mL),氮气置换三次,加热至100℃过夜,冷却至室温后用乙酸乙酯(20mL)稀释,硅藻土过滤,滤液用饱和食盐水(20mL×2)洗涤,有机相合并后用无水硫酸钠干燥,过滤,滤液浓缩后得到的粗产物用柱层析分离(石油醚:乙酸乙酯=3:1,V/V)得2-((4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)-2-甲基丙腈(0.12g,黄色油状物,产率:80%)。2-((3-Bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)-2-methylpropanenitrile (0.10 g, 0.24 mmol), 6-methyl -4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b] Pyridine (0.13 g, 0.24 mmol), potassium carbonate (0.066 g, 0.48 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.018 g, 0.024 mmol) dissolved in Dioxane (4 mL) and water (1 mL) were replaced with nitrogen three times, heated to 100 ° C overnight, cooled to room temperature, diluted with ethyl acetate (20 mL), filtered over Celite, and brine (20 mL×2 After washing, the organic phase is combined, dried over anhydrous sodium sulfate and filtered, and the crude product obtained by concentration of filtrate is separated by column chromatography ( petroleum ether: ethyl acetate = 3:1, V/V) to give 2-((4) -(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)sulfonyl) 2-methylpropionitrile (0.12 g, yellow oil, yield: 80%).
MS m/z(ESI):622.1[M+H] +. MS m/z (ESI): 6221. [M+H] + .
第八步:2-((4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺 酰)-2-甲基丙腈Step 8: 2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonyl-2-methylpropionitrile
Figure PCTCN2018073989-appb-000123
Figure PCTCN2018073989-appb-000123
室温下,将2-((4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)-2-甲基丙腈(0.10g,0.16mmol)溶解于乙醇(3mL)中,然后将甲醇钠(0.026g,0.48mmol)加入到反应体系中,加热至50℃,反应三小时。反应结束后,将乙醇旋干,残留物用乙酸乙酯(25mL)溶解,然后用盐水(15mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,将滤液旋干后得到的粗产物用制备板分离(石油醚:乙酸乙酯=1:1,V/V)得2-((4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)-2-甲基丙腈(0.06g,白色固体,产率80%)。2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 at room temperature -Phenyl)sulfonyl)-2-methylpropionitrile (0.10 g, 0.16 mmol) was dissolved in ethanol (3 mL), then sodium methoxide (0.026 g, 0.48 mmol) was added to the reaction system and heated to The reaction was carried out for three hours at 50 °C. After completion of the reaction, the ethanol was evaporated to dryness, and the residue was crystallised eluted with ethyl acetate (25mL), and then washed with brine (15mL × 2) Separation by preparative plate (petroleum ether: ethyl acetate = 1:1, V/V) gave 2-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrole) And [2,3-b]pyridin-4-yl)phenyl)sulfonyl)-2-methylpropanenitrile (0.06 g, white solid, yield 80%).
MS m/z(ESI):468.1[M+H] +. MS m / z (ESI): 468.1 [M + H] +.
第九步:4-(5-((2-氰基丙烷-2-基)磺酰)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物Step 9: 4-(5-((2-Cyanopropan-2-yl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrole And [2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000124
Figure PCTCN2018073989-appb-000124
冰浴下,将2-((4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)-2-甲基丙腈(0.06g,0.13mmol)溶解于四氢呋喃(5mL)中,然后将间氯过氧苯甲酸(0.031g,0.15mmol)加入到反应体系中,室温搅拌十分钟后,反应体系用乙酸乙酯(25mL)稀释,饱和碳酸氢钠水溶液(20mL)洗涤,盐水(20mL)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用反相制备色谱分离得到4-(5-((2-氰基丙烷-2-基)磺酰)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.025g,白色固体,产率40%)。2-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonyl)-2-methylpropionitrile (0.06 g, 0.13 mmol) was dissolved in tetrahydrofuran (5 mL), then m-chloroperoxybenzoic acid (0.031 g, 0.15 mmol) was added to the reaction system and stirred at room temperature. After a few minutes, the reaction was diluted with EtOAc EtOAc EtOAc EtOAc. Chromatography to give 4-(5-((2-cyanopropan-2-yl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrole [2,3-b]pyridine-7-oxide (0.025 g, white solid, yield 40%).
MS m/z(ESI):484.1[M+H] +. MS m/z (ESI): 484.1 [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.96(br,1H),8.20-8.16(m,1H),7.97-7.95(m,1H),7.40(s,1H),7.25-7.20(m,1H),7.17-7.11(m,1H),7.05-7.00(m,1H),6.97-6.92(m,2H),6.62(s,1H),2.78(s,3H),1.74(s,6H). 1 H NMR (400MHz, CDCl 3 ): δ11.96 (br, 1H), 8.20-8.16 (m, 1H), 7.97-7.95 (m, 1H), 7.40 (s, 1H), 7.25-7.20 (m, 1H), 7.17-7.11 (m, 1H), 7.05-7.00 (m, 1H), 6.97-6.92 (m, 2H), 6.62 (s, 1H), 2.78 (s, 3H), 1.74 (s, 6H) .
实施例24Example 24
4-(5-((氰基甲基)磺酰)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-((Cyanomethyl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide
Figure PCTCN2018073989-appb-000125
Figure PCTCN2018073989-appb-000125
第一步:2-((4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)乙酰腈First step: 2-((4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 -yl)phenyl)sulfonyl)acetonitrile
Figure PCTCN2018073989-appb-000126
Figure PCTCN2018073989-appb-000126
以2-((3-溴-4-(2,4-二氟苯氧基)苯基)磺酰)乙酰腈为反应原料,参照实施例23第七步,得到2-((4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)乙酰腈(0.056g,黄色固体,产率37%)。Taking 2-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)acetonitrile as the starting material, referring to the seventh step of Example 23, 2-((4-( 2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)sulfonyl)acetonitrile (0.056 g, yellow solid, yield 37%).
MS m/z(ESI):594.1[M+H] +. MS m/z (ESI): 594.1 [M+H] + .
第二步:2-((4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)乙酰腈Second step: 2-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonyl acetonitrile
Figure PCTCN2018073989-appb-000127
Figure PCTCN2018073989-appb-000127
室温下,将2-((4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)乙酰腈(0.03g,0.051mmol)溶解于N,N-二甲基甲酰胺(2mL)中,然后将氢化钠(60%,0.006g,0.10mmol)加入到反应液中,室温反应14小时后,反应液用乙酸乙酯(40mL)稀释,饱和食盐水(15mL×3)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用制备板分离(石油醚:乙酸乙酯=1:1,V/V)得到2-((4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)乙酰腈(0.015g,白色固体,产率68%)。2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 at room temperature -Phenyl)sulfonyl)acetonitrile (0.03 g, 0.051 mmol) was dissolved in N,N-dimethylformamide (2 mL), then sodium hydride (60%, 0.006 g, 0.10 mmol) After reacting for 14 hours at room temperature, the reaction mixture was diluted with ethyl acetate (40 mL), brine (15 mL×3), and the organic phase was dried over anhydrous sodium sulfate. Separation (petroleum ether: ethyl acetate = 1:1, V/V) gave 2-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2] , 3-b]pyridin-4-yl)phenyl)sulfonyl)acetonitrile (0.015 g, white solid, yield 68%).
MS m/z(ESI):440.1[M+H] +. MS m/z (ESI): 440.1 [M+H] + .
第三步:4-(5-((氰基甲基)磺酰)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并 [2,3-b]吡啶-7-氧化物Third step: 4-(5-((cyanomethyl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000128
Figure PCTCN2018073989-appb-000128
室温下,将2-((4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)乙酰腈(0.015g,0.034mmol)溶解于四氢呋喃(3mL)中,然后将间氯过氧苯甲酸(85%,0.008g,0.041mmol)加入到反应液中,反应十分钟后,反应液用乙酸乙酯(20mL)稀释,然后用饱和碳酸氢钠溶液洗涤(10mL×3),食盐水(10mL)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用反相制备色谱分离得到4-(5-((氰基甲基)磺酰)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.004g,白色固体,产率26%)。2-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) at room temperature Sulfonyl acetonitrile (0.015 g, 0.034 mmol) was dissolved in tetrahydrofuran (3 mL), then m-chloroperoxybenzoic acid (85%, 0.008 g, 0.041 mmol) was added to the reaction mixture and reacted for ten minutes. The solution was diluted with ethyl acetate (20 mL), EtOAc (EtOAc)EtOAc. Preparative chromatography to give 4-(5-((cyanomethyl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide (0.004 g, white solid, yield 26%).
MS m/z(ESI):456.1[M+H] +. MS m/z (ESI): 456.1 [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.51(br,1H),8.21(s,1H),8.00(d,J=8.8Hz,1H),7.44(s,1H),7.31(s,1H),7.16-7.07(m,1H),7.04-6.94(m,3H),6.65(s,1H),4.12(s,2H),2.80(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.51 (br, 1H), 8.21 (s, 1H), 8.00 (d, J = 8.8Hz, 1H), 7.44 (s, 1H), 7.31 (s, 1H ), 7.16-7.07 (m, 1H), 7.04-6.94 (m, 3H), 6.65 (s, 1H), 4.12 (s, 2H), 2.80 (s, 3H).
实施例25Example 25
4-(5-((1-氰基环丙基)磺酰)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-((1-Cyanocyclopropyl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000129
Figure PCTCN2018073989-appb-000129
第一步:1-((3-溴-4-(2,4-二氟苯氧基)苯基)磺酰)环丙烷-1-甲腈First step: 1-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)cyclopropane-1-carbonitrile
Figure PCTCN2018073989-appb-000130
Figure PCTCN2018073989-appb-000130
室温下,将2-((3-溴-4-(2,4-二氟苯氧基)苯基)磺酰)乙酰腈(0.10g,0.26mmol),1,2-二溴乙烷(0.097g,0.52mmol)和碳酸铯(0.17g,0.52mmol)溶解于四氢呋喃(8mL)中,加热至60℃,反应14小时。反应结束后,反应液用乙酸乙酯(25mL)稀释,饱和食盐水洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用制备板分离(石油醚:乙酸乙酯=3:1,V/V)得到1-((3-溴-4-(2,4-二氟苯氧基)苯基)磺酰)环 丙烷-1-甲腈(0.08g,无色油状物,产率75%)。2-((3-Bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)acetonitrile (0.10 g, 0.26 mmol), 1,2-dibromoethane ( 0.097 g, 0.52 mmol) and cesium carbonate (0.17 g, 0.52 mmol) were dissolved in tetrahydrofuran (8 mL) and heated to 60 ° C for 14 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc EtOAc EtOAc. 1, V/V) gave 1-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)cyclopropane-1-carbonitrile (0.08 g, m. Yield 75%).
第二步:1-((4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)环丙烷-1-甲腈Second step: 1-((4-(2,4-difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine-4 -yl)phenyl)sulfonyl)cyclopropane-1-carbonitrile
Figure PCTCN2018073989-appb-000131
Figure PCTCN2018073989-appb-000131
以1-((3-溴-4-(2,4-二氟苯氧基)苯基)磺酰)环丙烷-1-甲腈为反应原料,参照实施例23第七步,得1-((4-(2,4-二氟苯氧基)-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)环丙烷-1-甲腈(0.05g,白色固体,产率42%)。Taking 1-((3-bromo-4-(2,4-difluorophenoxy)phenyl)sulfonyl)cyclopropane-1-carbonitrile as the starting material, refer to the seventh step of Example 23 to obtain 1- ((4-(2,4-Difluorophenoxy)-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonylcyclopropane-1-carbonitrile (0.05 g, white solid, yield 42%).
MS m/z(ESI):620.1[M+H] +. MS m/z (ESI): 620.1 [M+H] + .
第三步:1-((4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)环丙烷-1-甲腈The third step: 1-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl) Sulfonylcyclopropane-1-carbonitrile
Figure PCTCN2018073989-appb-000132
Figure PCTCN2018073989-appb-000132
以1-((4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)环丙烷-1-甲腈为反应原料,参照实施例23第八步,得到1-((4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)环丙烷-1-甲腈(0.01g,白色固体,产率44%)。1-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)sulfonyl) Cyclopropane-1-carbonitrile was used as the starting material of the reaction. Referring to the eighth step of Example 23, 1-((4-(2,4-difluorophenoxy)-3-(6-methyl-1H-pyrrole was obtained. [2,3-b]pyridin-4-yl)phenyl)sulfonyl)cyclopropane-1-carbonitrile (0.01 g, white solid, yield 44%).
MS m/z(ESI):466.1[M+H] +. MS m/z (ESI): 466.1 [M+H] + .
第四步:4-(5-((1-氰基环丙基)磺酰)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物Fourth step: 4-(5-((1-cyanocyclopropyl)sulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[ 2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000133
Figure PCTCN2018073989-appb-000133
以1-((4-(2,4-二氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)磺酰)环丙烷-1-甲腈为反应原料,参照实施例23第九步,得到4-(5-((1-氰基环丙基)磺酰)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.0024g,白 色固体,产率24%)。1-((4-(2,4-Difluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)sulfonyl) Cyclopropane-1-carbonitrile is the starting material of the reaction, and the ninth step of Example 23 is obtained to obtain 4-(5-((1-cyanocyclopropyl)sulfonyl)-2-(2,4-difluorophenoxy). Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.0024 g, white solid, yield 24%).
MS m/z(ESI):482.1[M+H] +. MS m/z (ESI): 4821. [M+H] + .
1H NMR(400MHz,CDCl 3):δ10.55(br,1H),8.15(d,J=2.4Hz,1H),7.93(dd,J=8.8Hz,2.4Hz,1H),7.33-7.30(m,2H),7.17-7.10(m,1H),7.05-7.00(m,1H),6.97-6.91(m,2H),6.62(d,J=3.2Hz,1H),2.75(s,3H),1.98-1.94(m,2H),1.74-1.71(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ10.55 (br, 1H), 8.15 (d, J = 2.4Hz, 1H), 7.93 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.33-7.30 ( m, 2H), 7.17-7.10 (m, 1H), 7.05-7.00 (m, 1H), 6.97-6.91 (m, 2H), 6.62 (d, J = 3.2 Hz, 1H), 2.75 (s, 3H) , 1.98-1.94 (m, 2H), 1.74-1.71 (m, 2H).
实施例26Example 26
4-(2-(环己三烯并氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备4-(2-(cyclohexanetrienoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide preparation
Figure PCTCN2018073989-appb-000134
Figure PCTCN2018073989-appb-000134
第一步:(3-溴-4-氟苯基)(乙基)硫烷的制备First step: Preparation of (3-bromo-4-fluorophenyl)(ethyl)sulfane
Figure PCTCN2018073989-appb-000135
Figure PCTCN2018073989-appb-000135
3-溴-4-氟苯胺(19g,0.1mol)和铜粉(0.96g,15mmol)溶于1,2-二乙基二硫烷(50mL),将反应体系加热至80摄氏度。缓慢的滴入亚硝酸异戊酯(15g,0.15mmol)以保持反应的内部温度不高于90℃。滴加完毕反应在九90℃下搅拌两小时。反应液蒸干,甲苯和稀盐酸加入反应体系,分液,甲苯相分别使用稀盐酸,水和饱和食盐水洗涤,有机相干燥蒸干,残留物通过减压蒸馏,收集蒸汽温度60-70℃的馏分来得到的3-溴-4-氟苯基)(乙基)硫烷(15g,淡黄色油状,产率64%)。3-Bromo-4-fluoroaniline (19 g, 0.1 mol) and copper powder (0.96 g, 15 mmol) were dissolved in 1,2-diethyldisulfane (50 mL), and the reaction was heated to 80 °C. Isoamyl nitrite (15 g, 0.15 mmol) was slowly added dropwise to maintain the internal temperature of the reaction not higher than 90 °C. The reaction was completed and the mixture was stirred at 90 ° C for two hours. The reaction liquid is evaporated to dryness, and toluene and dilute hydrochloric acid are added to the reaction system, and the toluene phase is washed with dilute hydrochloric acid, water and saturated brine, and the organic phase is dried and evaporated to dryness, and the residue is subjected to distillation under reduced pressure to collect steam temperature 60-70 ° C. 3-Bromo-4-fluorophenyl)(ethyl)sulfane (15 g, pale yellow oil, yield 64%).
1H NMR(400MHz,CDCl3):δ7.53(dd,J=6.4Hz,2.0Hz,1H),7.27-7.23(m,1H),7.04(t,J=8.4Hz,1H),2.90(q,J=7.6Hz,2H),1.29(t,J=7.6Hz,3H). 1 H NMR (400MHz, CDCl3) : δ7.53 (dd, J = 6.4Hz, 2.0Hz, 1H), 7.27-7.23 (m, 1H), 7.04 (t, J = 8.4Hz, 1H), 2.90 (q , J = 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H).
第二步:2-溴-4-(乙基磺酰)-1-氟苯的制备The second step: preparation of 2-bromo-4-(ethylsulfonyl)-1-fluorobenzene
Figure PCTCN2018073989-appb-000136
Figure PCTCN2018073989-appb-000136
(3-溴-4-氟苯基)(乙基)硫烷(4.0g,17.09mmol),溶于二氯甲烷(50mL),0℃滴加间氯过氧苯甲酸(8.63g,37.61mmol)的二氯甲烷溶液(50mL)。反应在零度下搅拌一个小时后将反应液用饱和的硫代硫酸钠(50mL)洗,然后用饱和碳酸氢钠水溶液(100mL×2)、水(100mL×2)和饱和食盐水(100mL)洗涤,并用无水硫酸钠干燥,浓缩后柱层(石油醚:乙酸乙酯=3:1,V/V)析得到化合物2-溴-1- 氟-4-(乙基磺酰)苯(4.0g,产率88%)。(3-Bromo-4-fluorophenyl)(ethyl)sulfane (4.0 g, 17.09 mmol), dissolved in dichloromethane (50 mL), m. m. A solution of dichloromethane (50 mL). After the reaction was stirred at 0 °C for one hour, the reaction solution was washed with saturated sodium thiosulfate (50 mL) and then washed with saturated aqueous sodium hydrogen carbonate (100 mL×2), water (100 mL×2) and brine (100 mL) And dried over anhydrous sodium sulfate. After concentration, the column layer (petrole ether: ethyl acetate = 3:1, V/V) eluted to give compound 2-bromo-1-fluoro-4-(ethylsulfonyl)benzene (4.0 g, yield 88%).
第三步:4-(5-(乙基磺酰)-2-氟苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备Third step: Preparation of 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000137
Figure PCTCN2018073989-appb-000137
2-溴-4-(乙基磺酰)-1-氟苯(1.0g,4.43mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(1.83g,4.43mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(220mg,0.3mmol),碳酸钾(1.04g,7.52mmol)溶于1,4-二氧六环(16mL)和水(4mL),在氮气保护下100℃搅拌4小时。反应冷却至室温后,将反应液倒入水中(50mL),然后用乙酸乙酯萃取(50mL×2),合并有机相后用水洗(100mL),饱和食盐水洗(100mL),无水硫酸钠干燥,过滤,滤液浓缩后的粗品用柱层析(石油醚:乙酸乙酯=2:1,V/V)纯化得到化合物4-(5-(乙基磺酰)-2-氟苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(1.5g,产率72%)。2-bromo-4-(ethylsulfonyl)-1-fluorobenzene (1.0 g, 4.43 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.83 g, 4.43 mmol), [1,1'-bis(diphenylphosphine) Base) ferrocene] palladium dichloride (220 mg, 0.3 mmol), potassium carbonate (1.04 g, 7.52 mmol) dissolved in 1,4-dioxane (16 mL) and water (4 mL). Stir at °C for 4 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was poured into water (50 mL), and then ethyl acetate (50 mL×2), and the organic phase was combined, washed with water (100 mL), and brine (100 mL) The crude product was purified by column chromatography (petrole ether: ethyl acetate = 2:1, V/V) to afford compound 4-(5-(ethylsulfonyl)-2-fluorophenyl)- 6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.5 g, yield 72%).
第四步:4-(5-(乙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Fourth step: Preparation of 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000138
Figure PCTCN2018073989-appb-000138
4-(5-(乙基磺酰)-2-氟苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(600mg,1.27mmol)溶于叔丁醇(5mL)和四氢呋喃(2mL)中,加入氢氧化钾水溶液(3M,3mL),在70℃搅拌反应过夜后将反应液旋干,加入水(20mL),然后用乙酸乙酯萃取(20mL×2),合并有机相后依次用水(40mL)和饱和食盐水(40mL)洗涤,并用无水硫酸钠干燥,过滤浓缩后柱层析(石油醚:乙酸乙酯=1:1,V/V)得到4-(5-(乙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(320mg,产率79%)。4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (600 mg, 1.27 mmol) was dissolved To a solution of tert-butanol (5 mL) and tetrahydrofuran (2 mL), EtOAc (3M, 3 mL). 20 mL × 2), the organic phase was combined, washed with water (40 mL) and brine (40 mL) and dried over anhydrous sodium sulfate. V) 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (320 mg, yield 79%).
第五步:4-(5-(乙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 5: Preparation of 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000139
Figure PCTCN2018073989-appb-000139
4-(5-(乙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(280.0mg,0.88 mmol)溶于四氢呋喃(3mL)中,室温下加入间氯过氧苯甲酸(284mg,1.32mmol),室温下搅拌十分钟后将反应液用饱和硫代硫酸钠水溶液(20mL)淬灭,然后用用乙酸乙酯(20mL×2)萃取,有机相合并后用饱和碳酸氢钠水溶液(20mL)洗,水洗(20mL)和饱和食盐水(20mL)洗涤,并用无水硫酸钠干燥,过滤浓缩后用柱层析(二氯甲烷:甲醇=20:1,V/V)得到化合物4-(5-(乙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(220mg,产率75%)。4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (280.0 mg, 0.88 mmol) was dissolved in tetrahydrofuran (3 mL) m-Chloroperoxybenzoic acid (284 mg, 1.32 mmol) was added at room temperature, and the mixture was stirred for 10 min. The organic phase was combined and washed with saturated aqueous sodium hydrogen sulfate (20 mL), washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate. =20:1, V/V) gave the compound 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide (220 mg, yield 75%).
第六步:4-(2-(环己三烯并氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 6: 4-(2-(Cyclohexanetrienoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 - Preparation of oxides
Figure PCTCN2018073989-appb-000140
Figure PCTCN2018073989-appb-000140
将4-(5-(乙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(30.0mg,0.089mmol)溶于N,N-二甲基甲酰胺(2mL),冰浴下加入环己醇(18mg,0.18mmol),氢化钠(11mg,0.267mmol)。搅拌过夜后用氯化铵的水溶液(10mL)淬灭,然后用乙酸乙酯萃取(10mL×3),有机相合并后用水(10mL×2)和饱和食盐水(10mL)洗涤,并用无水硫酸钠干燥,浓缩后通过制备色谱得到化合物4-(2-(环己三烯并氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(15.4mg,产率41%)。Dissolving 4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (30.0 mg, 0.089 mmol) To a solution of N,N-dimethylformamide (2 mL), EtOAc (EtOAc) After stirring overnight, it was quenched with aqueous ammonium chloride (10 mL), and then ethyl acetate (10 mL×3). The organic phase was combined and washed with water (10 mL×2) and brine (10 mL) The sodium is dried and concentrated to give the compound 4-(2-(cyclohexanetrienoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide (15.4 mg, yield 41%).
1H NMR(400MHz,CDCl 3):δ11.75(s,1H),7.98(d,J=2.3Hz,1H),7.91(dd,J=8.7Hz,2.4Hz,1H),7.36(d,J=3.1Hz,1H),7.21–7.12(m,2H),6.45(d,J=3.3Hz,1H),4.56–4.37(m,1H),3.15(q,J=7.4Hz,2H),2.77(s,3H),1.88(s,2H),1.60(s,2H),1.56–1.46(m,3H),1.39–1.24(m,6H). 1 H NMR (400MHz, CDCl 3 ): δ11.75 (s, 1H), 7.98 (d, J = 2.3Hz, 1H), 7.91 (dd, J = 8.7Hz, 2.4Hz, 1H), 7.36 (d, J=3.1 Hz, 1H), 7.21–7.12 (m, 2H), 6.45 (d, J=3.3 Hz, 1H), 4.56–4.37 (m, 1H), 3.15 (q, J=7.4 Hz, 2H), 2.77 (s, 3H), 1.88 (s, 2H), 1.60 (s, 2H), 1.56 - 1.46 (m, 3H), 1.39 - 1.24 (m, 6H).
MS m/z(ESI):415.1[M+H] +MS m/z (ESI): 415.1 [M+H] + .
实施例27Example 27
4-(2-(环庚三烯并氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备4-(2-(cycloheptatrienoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide preparation
Figure PCTCN2018073989-appb-000141
Figure PCTCN2018073989-appb-000141
以环庚醇代替环己醇为原料,参照实施例26第六步,得到化合物4-(2-(环庚三烯并氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(18.0mg,产率49%)。Using cycloheptanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(2-(cycloheptatrienoxy)-5-(ethylsulfonyl)phenyl)-6- Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (18.0 mg, yield 49%).
1H NMR(400MHz,CDCl 3):δ12.37(s,1H),7.96(d,J=2.2Hz,1H),7.90(dd, J=8.7Hz,2.3Hz,1H),7.33(d,J=3.2Hz,1H),7.14(s,1H),7.09(d,J=8.8Hz,1H),6.40(d,J=3.2Hz,1H),4.62-4.58(m,1H),3.14(q,J=7.4Hz,2H),2.77(s,3H),1.95-1.92(m,,2H),1.74-1.72(m,2H),1.59-1.53(m,6H),1.42(dd,J=11.8,5.2Hz,2H),1.32(t,J=7.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.37 (s, 1H), 7.96 (d, J = 2.2Hz, 1H), 7.90 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.33 (d, J = 3.2 Hz, 1H), 7.14 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.40 (d, J = 3.2 Hz, 1H), 4.62-4.58 (m, 1H), 3.14 ( q, J = 7.4 Hz, 2H), 2.77 (s, 3H), 1.95-1.92 (m, 2H), 1.74-1.72 (m, 2H), 1.59-1.53 (m, 6H), 1.42 (dd, J =11.8, 5.2 Hz, 2H), 1.32 (t, J = 7.4 Hz, 3H).
MS m/z(ESI):429.1[M+H] +MS m/z (ESI): 429.1 [M+H] + .
实施例28Example 28
4-(2-((4,4-二氟环己基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备4-(2-((4,4-difluorocyclohexyl)oxo)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- Preparation of 7-oxide
Figure PCTCN2018073989-appb-000142
Figure PCTCN2018073989-appb-000142
以4,4-二氟环己烷-1-醇代替环己醇为原料,参照实施例26第六步,得到化合物4-(2-((4,4-二氟环己基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(13.0mg,产率32%)。Using 4,4-difluorocyclohexane-1-ol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(2-((4,4-difluorocyclohexyl)oxy)) was obtained. 5-(-Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (13.0 mg, yield 32%).
1H NMR(400MHz,CDCl 3):δ12.17(s,1H),8.00(d,J=2.2Hz,1H),7.93(dd,J=8.7Hz,2.3Hz,1H),7.34(d,J=3.3Hz,1H),7.16(d,J=8.8Hz,1H),7.10(s,1H),6.41(d,J=3.3Hz,1H),4.65(d,J=2.5Hz,1H),3.15(q,J=7.4Hz,2H),2.77(s,3H),1.99–1.78(m,8H),1.33(t,J=7.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.17 (s, 1H), 8.00 (d, J = 2.2Hz, 1H), 7.93 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.34 (d, J = 3.3 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 6.41 (d, J = 3.3 Hz, 1H), 4.65 (d, J = 2.5 Hz, 1H) , 3.15 (q, J = 7.4 Hz, 2H), 2.77 (s, 3H), 1.99 - 1.78 (m, 8H), 1.33 (t, J = 7.4 Hz, 3H).
MS m/z(ESI):451.1[M+H] +MS m / z (ESI): 451.1 [M + H] +.
实施例29Example 29
4-(5-(乙基磺酰)-2-(3-(三氟甲基)苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备4-(5-(ethylsulfonyl)-2-(3-(trifluoromethyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 - Preparation of oxides
Figure PCTCN2018073989-appb-000143
Figure PCTCN2018073989-appb-000143
第一步:4-(5-(乙基磺酰)-2-(3-(三氟甲基)苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备First step: 4-(5-(ethylsulfonyl)-2-(3-(trifluoromethyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b Preparation of pyridine-7-oxide
Figure PCTCN2018073989-appb-000144
Figure PCTCN2018073989-appb-000144
4-(5-(乙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(30.0mg,0.089mmol)溶于N-甲基吡咯烷酮(2mL),冰浴下加入3-(三氟甲基)苯酚((32mg,0.18mmol),碳酸铯(87mg,0.267mmol)。微波180℃下反应30分钟后降至室温,然后用氯化铵的水溶液(20mL)淬灭,然后用乙酸乙酯萃取(10mL×3)。有机相合并后用水(10mL×2)和饱和食盐水(10mL)洗涤,并用无水硫酸钠干燥,浓缩后通过制备色谱得到化合物4-(5-(乙基磺酰)-2-(3-(三氟甲基)苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(11.0mg,产率26%)。4-(5-(ethylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (30.0 mg, 0.089 mmol) was dissolved N-methylpyrrolidone (2 mL), 3-(trifluoromethyl)phenol ((32 mg, 0.18 mmol), cesium carbonate (87 mg, 0.267 mmol) was added under ice-cooling. It is then quenched with aqueous ammonium chloride (20 mL), and then ethyl acetate (10 mL, 3). The organic phase is combined and washed with water (10 mL×2) and brine (10 mL) Drying, concentration and preparative chromatography to give the compound 4-(5-(ethylsulfonyl)-2-(3-(trifluoromethyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[ 2,3-b]pyridine-7-oxide (11.0 mg, yield 26%).
1H NMR(400MHz,CDCl 3):δ13.38(s,1H),8.14(d,J=2.2Hz,1H),7.92(dd,J=8.6Hz,2.3Hz,1H),7.48–7.29(m,3H),7.19(s,1H),7.14(d,J=6.1Hz,3H),6.45(d,J=2.9Hz,1H),3.19(q,J=7.3Hz,2H),2.76(s,3H),1.40–1.28(m,3H). 1 H NMR (400MHz, CDCl 3 ): δ13.38 (s, 1H), 8.14 (d, J = 2.2Hz, 1H), 7.92 (dd, J = 8.6Hz, 2.3Hz, 1H), 7.48-7.29 ( m, 3H), 7.19 (s, 1H), 7.14 (d, J = 6.1 Hz, 3H), 6.45 (d, J = 2.9 Hz, 1H), 3.19 (q, J = 7.3 Hz, 2H), 2.76 ( s, 3H), 1.40–1.28 (m, 3H).
MS m/z(ESI):477.1[M+H] +MS m/z (ESI): 477.1 [M+H] + .
实施例30Example 30
4-(2-((3,3-二氟环丁基)甲氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备4-(2-((3,3-Difluorocyclobutyl)methoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Preparation of pyridine-7-oxide
Figure PCTCN2018073989-appb-000145
Figure PCTCN2018073989-appb-000145
以(3,3-二氟环丁基)甲醇代替环己醇为原料,参照实施例26第六步,得到化合物4-(2-((3,3-二氟环丁基)甲氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(14.0mg,产率36%)。Using (3,3-difluorocyclobutyl)methanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(2-((3,3-difluorocyclobutyl)methoxy) was obtained. 5-(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (14.0 mg, yield 36%).
1H NMR(400MHz,CDCl 3):δ12.65(s,1H),8.20–7.81(m,2H),7.34(d,J=3.3Hz,1H),7.16(d,J=8.7Hz,1H),7.10(s,1H),6.34(d,J=3.3Hz,1H),4.12(d,J=5.7Hz,2H),3.15(q,J=7.4Hz,2H),2.78(s,3H),2.55-2.51(m,3H),2.39–2.16(m,2H),1.32(t,J=7.4Hz,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 12.65 (s, 1H), 8.20 - 7.81 (m, 2H), 7.34 (d, J = 3.3 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H) ), 7.10 (s, 1H), 6.34 (d, J = 3.3 Hz, 1H), 4.12 (d, J = 5.7 Hz, 2H), 3.15 (q, J = 7.4 Hz, 2H), 2.78 (s, 3H) ), 2.55-2.51 (m, 3H), 2.39 - 2.16 (m, 2H), 1.32 (t, J = 7.4 Hz, 3H).
MS m/z(ESI):437.1[M+H] +MS m/z (ESI): 437.1 [M+H] + .
实施例31Example 31
4-(2-(环丁基)甲氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备4-(2-(cyclobutyl)methoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide preparation
Figure PCTCN2018073989-appb-000146
Figure PCTCN2018073989-appb-000146
以环丁基甲醇代替环己醇为原料,参照实施例26第六步,得到化合物4-(2-(环丁基)甲氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物 (19.0mg,产率53%)。Starting from cyclohexanol in place of cyclohexanol, the sixth step of Example 26 was carried out to obtain the compound 4-(2-(cyclobutyl)methoxy)-5-(ethylsulfonyl)phenyl)-6. Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (19.0 mg, yield 53%).
1H NMR(400MHz,CDCl 3):δ12.88(s,1H),7.93(d,J=2.3Hz,1H),7.85(dd,J=8.7,2.4Hz,1H),7.26(d,J=3.1Hz,1H),7.13–7.03(m,2H),6.32(d,J=3.2Hz,1H),3.96(d,J=6.3Hz,2H),3.07(q,J=7.4Hz,2H),2.71(s,3H),2.65–2.55(m,1H),1.93-1.91(m,2H),1.86–1.76(m,1H),1.76–1.66(m,3H),1.24(t,J=7.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.88 (s, 1H), 7.93 (d, J = 2.3Hz, 1H), 7.85 (dd, J = 8.7,2.4Hz, 1H), 7.26 (d, J =3.1 Hz, 1H), 7.13 - 7.03 (m, 2H), 6.32 (d, J = 3.2 Hz, 1H), 3.96 (d, J = 6.3 Hz, 2H), 3.07 (q, J = 7.4 Hz, 2H) ), 2.71 (s, 3H), 2.65 - 2.55 (m, 1H), 1.93-1.91 (m, 2H), 1.86 - 1.76 (m, 1H), 1.76 - 1.66 (m, 3H), 1.24 (t, J =7.4Hz, 3H).
MS m/z(ESI):401.1[M+H] +MS m/z (ESI): 401.1 [M+H] + .
实施例32Example 32
4-(2-(2,4-二氟苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxidation Object
Figure PCTCN2018073989-appb-000147
Figure PCTCN2018073989-appb-000147
以2,4-二氟苯酚代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(2-(2,4-二氟苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(16.0mg,产率40%)。Starting from 2,4-difluorophenol instead of 3-(trifluoromethyl)phenol, referring to Example 29, the compound 4-(2-(2,4-difluorophenoxy)-5-(ethyl) was obtained. Sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (16.0 mg, yield 40%).
1H NMR(400MHz,CD 3OD):δ7.97(d,J=2.3Hz,1H),7.83(dd,J=8.7Hz,2.3Hz,1H),7.33(d,J=3.4Hz,1H),7.26(s,1H),7.13(td,J=9.1Hz,5.4Hz,1H),7.05(ddd,J=11.2Hz,8.6Hz,2.9Hz,1H),6.96(dd,J=8.7Hz,0.7Hz,1H),6.91–6.84(m,1H),6.46(d,J=3.4Hz,1H),3.21–3.16(m,2H),2.60(s,3H),1.17(q,J=7.3Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ 7.97 (d, J = 2.3 Hz, 1H), 7.83 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 7.33 (d, J = 3.4 Hz, 1H) ), 7.26 (s, 1H), 7.13 (td, J = 9.1 Hz, 5.4 Hz, 1H), 7.05 (ddd, J = 11.2 Hz, 8.6 Hz, 2.9 Hz, 1H), 6.96 (dd, J = 8.7 Hz) , 0.7 Hz, 1H), 6.91 - 6.84 (m, 1H), 6.46 (d, J = 3.4 Hz, 1H), 3.21 - 3.16 (m, 2H), 2.60 (s, 3H), 1.17 (q, J = 7.3Hz, 3H).
MS m/z(ESI):445.1[M+H] +MS m/z (ESI): 445.1 [M+H] + .
实施例33Example 33
4-(2-(4-溴-2-氟苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-Bromo-2-fluorophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide
Figure PCTCN2018073989-appb-000148
Figure PCTCN2018073989-appb-000148
以4-溴-2-氟苯酚代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(2-(2,4-二氟苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(13.0mg,产率29%)。Using 4-bromo-2-fluorophenol instead of 3-(trifluoromethyl)phenol as the starting material, referring to Example 29, the compound 4-(2-(2,4-difluorophenoxy)-5-(B) was obtained. Sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (13.0 mg, yield 29%).
1H NMR(400MHz,CD 3OD):δ8.02–7.89(m,1H),7.86(dd,J=8.7Hz,2.3 Hz,1H),7.38(dd,J=10.2Hz,2.3Hz,1H),7.33(d,J=3.4Hz,1H),7.23(d,J=8.9Hz,2H),7.01(dd,J=16.8Hz,8.5Hz,2H),6.47–6.38(m,1H),3.21(dd,J=3.2Hz,1.6Hz,2H),2.59(s,3H),1.17(t,J=7.4Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ 8.02 - 7.89 (m, 1H), 7.86 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 7.38 (dd, J = 10.2 Hz, 2.3 Hz, 1H) ), 7.33 (d, J = 3.4 Hz, 1H), 7.23 (d, J = 8.9 Hz, 2H), 7.01 (dd, J = 16.8 Hz, 8.5 Hz, 2H), 6.47 - 6.38 (m, 1H), 3.21 (dd, J = 3.2 Hz, 1.6 Hz, 2H), 2.59 (s, 3H), 1.17 (t, J = 7.4 Hz, 3H).
MS m/z(ESI):505.1[M+H] +MS m/z (ESI): 505.1 [M+H] + .
实施例34Example 34
4-(5-(乙基磺酰)-2-(((1s,4s)-4-羟基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(ethylsulfonyl)-2-(((1s,4s)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide
Figure PCTCN2018073989-appb-000149
Figure PCTCN2018073989-appb-000149
以(1s,4s)-环己烷-1,4-二醇代替环己醇为原料,参照实施例26第六步,得到化合物4-(5-(乙基磺酰)-2-(((1s,4s)-4-羟基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(4.5mg,产率12%)。Using (1s, 4s)-cyclohexane-1,4-diol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(5-(ethylsulfonyl)-2-(( (1s, 4s)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (4.5 mg, yield 12%) .
1H NMR(400MHz,CDCl 3):δ11.98(s,1H),8.01(d,J=2.4Hz,1H),7.91(dd,J=8.7Hz,2.4Hz,1H),7.29(d,J=3.3Hz,1H),7.15(dd,J=17.3Hz,8.4Hz,2H),6.43(d,J=3.3Hz,1H),4.55(s,1H),3.70(d,J=8.6Hz,1H),3.15(q,J=7.4Hz,2H),2.77(d,J=9.0Hz,3H),2.01–1.89(m,2H),1.72–1.57(m,4H),1.50–1.37(m,2H),1.34–1.28(m,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 11.98 (s, 1H), 8.1 (d, J = 2.4 Hz, 1H), 7.91 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 7.29 (d, J = 3.3 Hz, 1H), 7.15 (dd, J = 17.3 Hz, 8.4 Hz, 2H), 6.43 (d, J = 3.3 Hz, 1H), 4.55 (s, 1H), 3.70 (d, J = 8.6 Hz) , 1H), 3.15 (q, J = 7.4 Hz, 2H), 2.77 (d, J = 9.0 Hz, 3H), 2.01 - 1.89 (m, 2H), 1.72 - 1.57 (m, 4H), 1.50 - 1.37 ( m, 2H), 1.34–1.28 (m, 3H).
MS m/z(ESI):431.1[M+H] +MS m/z (ESI): 431.1 [M+H] + .
实施例35Example 35
4-(2-(4-环丙基苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-cyclopropylphenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000150
Figure PCTCN2018073989-appb-000150
以4-环丙基苯酚代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(2-(4-环丙基苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(10.0mg,产率25%)。Using 4-cyclopropylphenol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-(4-cyclopropylphenoxy)-5-(ethylsulfonyl) was obtained. Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (10.0 mg, yield 25%).
1H NMR(400MHz,CDCl 3):δ12.16(s,1H),8.06(d,J=2.2Hz,1H),7.81(dd,J=8.7Hz,2.3Hz,1H),7.30(d,J=3.3Hz,1H),7.16(s,1H),7.07(d,J=8.6Hz,2H),7.01(d,J=8.7Hz,1H),6.90(d,J=8.6Hz,2H),6.49(d,J=3.3Hz,1H),3.15(q,J=7.4Hz,2H),2.74(s,3H),1.89(td,J=8.4Hz,4.2Hz,1H),1.33(t,J=7.4Hz,3H),1.03–0.92(m,2H),0.71–0.61(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ12.16 (s, 1H), 8.06 (d, J = 2.2Hz, 1H), 7.81 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.30 (d, J = 3.3 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 8.6 Hz, 2H) , 6.49 (d, J = 3.3 Hz, 1H), 3.15 (q, J = 7.4 Hz, 2H), 2.74 (s, 3H), 1.89 (td, J = 8.4 Hz, 4.2 Hz, 1H), 1.33 (t , J = 7.4 Hz, 3H), 1.03 - 0.92 (m, 2H), 0.71 - 0.61 (m, 2H).
MS m/z(ESI):449.1[M+H] +MS m/z (ESI): 449.1 [M+H] + .
实施例36Example 36
4-(5-(乙基磺酰)-2-((1-(三氟甲基)环丙基)甲氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(ethylsulfonyl)-2-((1-(trifluoromethyl)cyclopropyl)methoxy)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000151
Figure PCTCN2018073989-appb-000151
以(1-(三氟甲基)环丙基)甲醇代替环己醇为原料,参照实施例26第六步,得到化合物4-(5-(乙基磺酰)-2-((1-(三氟甲基)环丙基)甲氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(20.9mg,产率52%)。Using (1-(trifluoromethyl)cyclopropyl)methanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(5-(ethylsulfonyl)-2-((1- (Trifluoromethyl)cyclopropyl)methoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (20.9 mg, yield 52%).
1H NMR(400MHz,CDCl 3):δ13.12(s,1H),8.04(d,J=2.3Hz,1H),7.93(dd,J=8.7Hz,2.3Hz,1H),7.34(d,J=3.3Hz,1H),7.22(s,1H),7.13(d,J=8.8Hz,1H),6.38(d,J=3.3Hz,1H),4.20(s,2H),3.14(q,J=7.4Hz,2H),2.78(s,3H),1.31(t,J=7.4Hz,3H),1.02(t,J=6.2Hz,2H),0.73(s,2H). 1 H NMR (400MHz, CDCl 3 ): δ13.12 (s, 1H), 8.04 (d, J = 2.3Hz, 1H), 7.93 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.34 (d, J = 3.3 Hz, 1H), 7.22 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 6.38 (d, J = 3.3 Hz, 1H), 4.20 (s, 2H), 3.14 (q, J = 7.4 Hz, 2H), 2.78 (s, 3H), 1.31 (t, J = 7.4 Hz, 3H), 1.02 (t, J = 6.2 Hz, 2H), 0.73 (s, 2H).
MS m/z(ESI):455.1[M+H] +MS m/z (ESI): 455.1 [M+H] + .
实施例37Example 37
4-(2-((4,4-二甲基环己基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((4,4-Dimethylcyclohexyl)oxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide
Figure PCTCN2018073989-appb-000152
Figure PCTCN2018073989-appb-000152
以4,4-二甲基环己烷-1-醇代替环己醇为原料,参照实施例26第六步,得到化合物4-(2-((4,4-二甲基环己基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(10.0mg,产率25%)。Using 4,4-dimethylcyclohexane-1-ol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(2-((4,4-dimethylcyclohexyl))oxy) was obtained. 5)(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (10.0 mg, yield 25%).
1H NMR(400MHz,CDCl 3):δ11.97(s,1H),7.99(d,J=2.3Hz,1H),7.89(dd,J=8.7Hz,2.3Hz,1H),7.29(d,J=3.3Hz,1H),7.17–7.11(m,2H),6.42(d,J=3.3Hz,1H),4.44(dd,J=7.3Hz,3.7Hz,1H),3.14(q,J=7.4Hz,2H),2.77(s,3H),1.83–1.75(m,2H),1.62(ddd,J=16.8Hz,12.7Hz,3.8Hz,2H),1.38–1.27(m,5H),1.19(ddd,J=13.2,9.0,3.9Hz,2H),0.91(s,3H),0.83(s,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.97 (s, 1H), 7.99 (d, J = 2.3Hz, 1H), 7.89 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.29 (d, J=3.3 Hz, 1H), 7.17–7.11 (m, 2H), 6.42 (d, J=3.3 Hz, 1H), 4.44 (dd, J=7.3 Hz, 3.7 Hz, 1H), 3.14 (q, J= 7.4 Hz, 2H), 2.77 (s, 3H), 1.83 - 1.75 (m, 2H), 1.62 (ddd, J = 16.8 Hz, 12.7 Hz, 3.8 Hz, 2H), 1.38 - 1.27 (m, 5H), 1.19 (ddd, J = 13.2, 9.0, 3.9 Hz, 2H), 0.91 (s, 3H), 0.83 (s, 3H).
MS m/z(ESI):443.1[M+H] +MS m/z (ESI): 443.1 [M+H] + .
实施例38Example 38
4-(2-(4-氯-2-氟苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化 物4-(2-(4-Chloro-2-fluorophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide
Figure PCTCN2018073989-appb-000153
Figure PCTCN2018073989-appb-000153
以4-氯-2-氟苯酚代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(2-(4-氯-2-氟苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(13.2mg,产率32%)。4-Chloro-2-fluorophenol was used instead of 3-(trifluoromethyl)phenol as the starting material, and Example 29 was obtained to obtain the compound 4-(2-(4-chloro-2-fluorophenoxy)-5-( Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (13.2 mg, yield 32%).
1H NMR(400MHz,CDCl 3):δ12.28(s,1H),8.10(s,1H),7.87(d,J=8.5Hz,1H),7.31(s,1H),7.26(s,1H),7.22(d,J=7.5Hz,1H),7.13(d,J=8.7Hz,1H),7.02(t,J=8.4Hz,1H),6.95(d,J=8.6Hz,1H),6.50(d,J=2.5Hz,1H),3.16(q,J=7.3Hz,2H),2.77(s,3H),1.34(t,J=7.3Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.28 (s, 1H), 8.10 (s, 1H), 7.87 (d, J = 8.5Hz, 1H), 7.31 (s, 1H), 7.26 (s, 1H ), 7.22 (d, J = 7.5 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 7.02 (t, J = 8.4 Hz, 1H), 6.95 (d, J = 8.6 Hz, 1H), 6.50 (d, J = 2.5 Hz, 1H), 3.16 (q, J = 7.3 Hz, 2H), 2.77 (s, 3H), 1.34 (t, J = 7.3 Hz, 3H).
MS m/z(ESI):461.1[M+H] +MS m/z (ESI): 461.1 [M+H] + .
实施例39Example 39
4-(2-((1H-吲哚-6-基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((1H-吲哚-6-yl)oxo)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000154
Figure PCTCN2018073989-appb-000154
以1H-吲哚-6-酚代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(2-((1H-吲哚-6-基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(12.2mg,产率31%)。Using 1H-indole-6-phenol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-((1H-indol-6-yl)oxy)-5 was obtained. -(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (12.2 mg, yield 31%).
1H NMR(400MHz,CDCl 3):δ12.75(s,1H),8.97(s,1H),8.05(s,1H),7.75(d,J=8.7Hz,1H),7.58(d,J=8.5Hz,1H),7.31–7.16(m,3H),7.09(s,1H),6.98(d,J=8.8Hz,1H),6.80(d,J=8.5Hz,1H),6.50(d,J=8.4Hz,2H),3.14(q,J=7.3Hz,2H),2.68(s,3H),1.31(t,J=7.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.75 (s, 1H), 8.97 (s, 1H), 8.05 (s, 1H), 7.75 (d, J = 8.7Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.31 - 7.16 (m, 3H), 7.09 (s, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.50 (d , J = 8.4 Hz, 2H), 3.14 (q, J = 7.3 Hz, 2H), 2.68 (s, 3H), 1.31 (t, J = 7.4 Hz, 3H).
MS m/z(ESI):448.1[M+H] +MS m/z (ESI): 448.1 [M+H] + .
实施例40Example 40
4-(2-(4-氨基甲酰苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-carbamoylphenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000155
Figure PCTCN2018073989-appb-000155
以4-羟基苯酰胺代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(2-(4-氨基甲酰苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(22.2mg,产率55%)。Using 4-hydroxybenzamide instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-(4-carbamoylphenoxy)-5-(ethylsulfonyl) was obtained. Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (22.2 mg, 55% yield).
1H NMR(400MHz,CD 3OD):δ8.04(d,J=2.3Hz,1H),7.94(dd,J=8.6Hz,2.3Hz,1H),7.72(d,J=2.1Hz,1H),7.71(d,J=2.1Hz,1H),7.35(d,J=3.4Hz,1H),7.27(d,J=8.6Hz,1H),7.22(s,1H),6.98–6.84(m,2H),6.47(d,J=3.4Hz,1H),3.25(s,3H),2.56(s,3H),1.21(t,J=7.4Hz,4H). 1 H NMR (400 MHz, CD 3 OD): δ 8.04 (d, J = 2.3 Hz, 1H), 7.94 (dd, J = 8.6 Hz, 2.3 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H) ), 7.71 (d, J = 2.1 Hz, 1H), 7.35 (d, J = 3.4 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 7.22 (s, 1H), 6.98 - 6.84 (m) , 2H), 6.47 (d, J = 3.4 Hz, 1H), 3.25 (s, 3H), 2.56 (s, 3H), 1.21 (t, J = 7.4 Hz, 4H).
MS m/z(ESI):452.1[M+H] +MS m/z (ESI): 4521. [M+H] + .
实施例41Example 41
4-(2-(4-(叔-丁基)苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-(tert-butyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 -oxide
Figure PCTCN2018073989-appb-000156
Figure PCTCN2018073989-appb-000156
以4-羟基苯酰胺代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(2-(4-(叔-丁基)苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(22.5mg,产率55%)。Using 4-hydroxybenzamide instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-(4-(tert-butyl)phenoxy)-5-(ethyl) was obtained. Sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (22.5 mg, yield 55%).
1H NMR(400MHz,CDCl 3):δ13.22(s,1H),8.10(d,J=2.3Hz,1H),7.83(dd,J=8.7Hz,2.3Hz,1H),7.37(d,J=8.7Hz,2H),7.32(d,J=3.2Hz,1H),7.21(s,1H),7.06(d,J=8.7Hz,1H),6.95(d,J=8.7Hz,2H),6.49(d,J=3.2Hz,1H),3.16(q,J=7.4Hz,2H),2.77(s,3H),1.36–1.23(m,12H). 1 H NMR (400MHz, CDCl 3 ): δ13.22 (s, 1H), 8.10 (d, J = 2.3Hz, 1H), 7.83 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.37 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 3.2 Hz, 1H), 7.21 (s, 1H), 7.06 (d, J = 8.7 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H) , 6.49 (d, J = 3.2 Hz, 1H), 3.16 (q, J = 7.4 Hz, 2H), 2.77 (s, 3H), 1.36 - 1.23 (m, 12H).
MS m/z(ESI):465.1[M+H] +MS m/z (ESI): 465.1 [M+H] + .
实施例42Example 42
4-(5-(乙基磺酰)-2-(噻吩-3-基甲氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(ethylsulfonyl)-2-(thiophen-3-ylmethoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000157
Figure PCTCN2018073989-appb-000157
以噻吩-3-基甲醇代替环己醇为原料,参照实施例26第六步,得到化合物4-(5-(乙基磺酰)-2-(噻吩-3-基甲氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(20.0mg,产率53%)。Using thiophen-3-ylmethanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(5-(ethylsulfonyl)-2-(thiophen-3-ylmethoxy)phenyl was obtained. 6-Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (20.0 mg, yield 53%).
1H NMR(400MHz,CDCl 3):δ12.25(s,1H),8.01(d,J=2.3Hz,1H),7.94(dd,J=8.7Hz,2.3Hz,1H),7.32–7.27(m,2H),7.25(d,J=8.8Hz,1H),7.21–7.04(m, 2H),7.08–6.86(m,1H),6.39(d,J=3.3Hz,1H),5.21(s,2H),3.15(q,J=7.4Hz,2H),2.75(s,3H),1.32(t,J=7.4Hz,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 12.25 (s, 1H), 8.1 (d, J = 2.3 Hz, 1H), 7.94 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 7.32 - 7.27 ( m, 2H), 7.25 (d, J = 8.8 Hz, 1H), 7.21 - 7.04 (m, 2H), 7.08 - 6.86 (m, 1H), 6.39 (d, J = 3.3 Hz, 1H), 5.21 (s) , 2H), 3.15 (q, J = 7.4 Hz, 2H), 2.75 (s, 3H), 1.32 (t, J = 7.4 Hz, 3H).
MS m/z(ESI):429.1[M+H] +MS m/z (ESI): 429.1 [M+H] + .
实施例43Example 43
4-(2-(4-环丙基-2-氟苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-Cyclopropyl-2-fluorophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000158
Figure PCTCN2018073989-appb-000158
以4-环丙基-2-氟苯酚代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(2-(4-环丙基-2-氟苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(10.5mg,产率25%)。Using 4-cyclopropyl-2-fluorophenol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-(4-cyclopropyl-2-fluorophenoxy) was obtained. 5-(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (10.5 mg, yield 25%).
1H NMR(400MHz,CD 3OD):δ8.09(d,J=2.3Hz,1H),7.94(dd,J=8.8Hz,2.4Hz,1H),7.46(d,J=3.4Hz,1H),7.39(s,1H),7.07(dt,J=8.5Hz,4.7Hz,2H),7.02–6.92(m,2H),6.60(d,J=3.5Hz,1H),3.29(q,J=7.4Hz,2H),2.73(s,3H),1.95(dq,J=8.5Hz,5.1Hz,1H),1.29(t,J=7.4Hz,3H),1.09–0.93(m,2H),0.83–0.55(m,2H). 1 H NMR (400 MHz, CD 3 OD): δ 8.09 (d, J = 2.3 Hz, 1H), 7.94 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.46 (d, J = 3.4 Hz, 1H) ), 7.39 (s, 1H), 7.07 (dt, J = 8.5 Hz, 4.7 Hz, 2H), 7.02 - 6.92 (m, 2H), 6.60 (d, J = 3.5 Hz, 1H), 3.29 (q, J) = 7.4 Hz, 2H), 2.73 (s, 3H), 1.95 (dq, J = 8.5 Hz, 5.1 Hz, 1H), 1.29 (t, J = 7.4 Hz, 3H), 1.09 - 0.93 (m, 2H), 0.83–0.55 (m, 2H).
MS m/z(ESI):467.1[M+H] +MS m/z (ESI): 467.1 [M+H] + .
实施例44Example 44
4-(2-((1H-吲哚-5-基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((1H-indol-5-yl)oxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000159
Figure PCTCN2018073989-appb-000159
以1H-吲哚-5-酚代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(2-((1H-吲哚-5-基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(10.0mg,产率25%)。Using 1H-indole-5-phenol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-((1H-indol-5-yl)oxy)-5 was obtained. -(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (10.0 mg, yield 25%).
1H NMR(400MHz,CD 3OD):δ8.08(d,J=2.3Hz,1H),7.87(dd,J=8.8Hz,2.4Hz,1H),7.46(dd,J=15.7Hz,6.6Hz,3H),7.30(dd,J=9.4Hz,2.7Hz,2H),7.05(d,J=8.8Hz,1H),6.87(dd,J=8.7Hz,2.3Hz,1H),6.66(d,J=3.4Hz,1H),6.46(dd,J=3.1Hz,0.8Hz,1H),3.27(q,J=7.4Hz,2H),2.74(s,3H),1.29(t,J=7.4Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ 8.08 (d, J = 2.3 Hz, 1H), 7.78 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.46 (dd, J = 15.7 Hz, 6.6 Hz, 3H), 7.30 (dd, J = 9.4 Hz, 2.7 Hz, 2H), 7.05 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 6.66 (d , J = 3.4 Hz, 1H), 6.46 (dd, J = 3.1 Hz, 0.8 Hz, 1H), 3.27 (q, J = 7.4 Hz, 2H), 2.74 (s, 3H), 1.29 (t, J = 7.4) Hz, 3H).
MS m/z(ESI):448.1[M+H] +MS m/z (ESI): 448.1 [M+H] + .
实施例45Example 45
4-(5-(乙基磺酰)-2-(4-(三氟甲基)苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(ethylsulfonyl)-2-(4-(trifluoromethyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 -oxide
Figure PCTCN2018073989-appb-000160
Figure PCTCN2018073989-appb-000160
以4-(三氟甲基)苯酚代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(5-(乙基磺酰)-2-(4-(三氟甲基)苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(8.0mg,产率19%)。4-(Trifluoromethyl)phenol was used as a starting material instead of 3-(trifluoromethyl)phenol. Referring to Example 29, the compound 4-(5-(ethylsulfonyl)-2-(4-trifluoro) was obtained. Methyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (8.0 mg, yield 19%).
1H NMR(400MHz,CDCl 3):δ12.55(s,1H),8.12(s,1H),7.99(d,J=8.6Hz,1H),7.66(d,J=7.9Hz,2H),7.53(d,J=10.9Hz,1H),7.27(s,1H),7.19(d,J=8.6Hz,1H),7.10(d,J=8.1Hz,2H),6.61(s,1H),3.20(d,J=6.9Hz,2H),2.90(s,3H),1.37(t,J=6.3Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.55 (s, 1H), 8.12 (s, 1H), 7.99 (d, J = 8.6Hz, 1H), 7.66 (d, J = 7.9Hz, 2H), 7.53 (d, J = 10.9 Hz, 1H), 7.27 (s, 1H), 7.19 (d, J = 8.6 Hz, 1H), 7.10 (d, J = 8.1 Hz, 2H), 6.61 (s, 1H), 3.20 (d, J = 6.9 Hz, 2H), 2.90 (s, 3H), 1.37 (t, J = 6.3 Hz, 3H).
MS m/z(ESI):477.1[M+H] +MS m/z (ESI): 477.1 [M+H] + .
实施例46Example 46
4-(5-(乙基磺酰)-2-(((1r,4r)-4-羟基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(ethylsulfonyl)-2-(((1r,4r)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide
Figure PCTCN2018073989-appb-000161
Figure PCTCN2018073989-appb-000161
以(1r,4r)-环己烷-1,4-二醇代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(5-(乙基磺酰)-2-(((1r,4r)-4-羟基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(3.0mg,产率8%)。Using (1r,4r)-cyclohexane-1,4-diol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(5-(ethylsulfonyl)-2 was obtained. -(((1r,4r)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (3.0 mg, yield 8%).
1H NMR(400MHz,CD 3OD):δ7.85(dt,J=5.7Hz,2.4Hz,2H),7.29(dd,J=34.4Hz,31.1Hz,2H),7.17(s,1H),6.34(d,J=3.4Hz,1H),4.56–4.38(m,1H),3.60–3.37(m,1H),3.14(q,J=7.4Hz,2H),2.60(s,3H),2.01–1.91(m,2H),1.75–1.52(m,2H),1.33(td,J=13.2Hz,2.7Hz,4H),1.16(t,J=7.4Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ 7.85 (dt, J = 5.7 Hz, 2.4 Hz, 2H), 7.29 (dd, J = 34.4 Hz, 31.1 Hz, 2H), 7.17 (s, 1H), 6.34 (d, J = 3.4 Hz, 1H), 4.56 - 4.38 (m, 1H), 3.60 - 3.37 (m, 1H), 3.14 (q, J = 7.4 Hz, 2H), 2.60 (s, 3H), 2.01 –1.91 (m, 2H), 1.75–1.52 (m, 2H), 1.33 (td, J = 13.2 Hz, 2.7 Hz, 4H), 1.16 (t, J = 7.4 Hz, 3H).
MS m/z(ESI):431.1[M+H] +MS m/z (ESI): 431.1 [M+H] + .
实施例47Example 47
4-(2-((1H-吲唑-5-基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((1H-carbazol-5-yl)oxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000162
Figure PCTCN2018073989-appb-000162
以1H-吲唑-5-醇代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(2-((1H-吲唑-5-基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(5.0mg,产率13%)。Using 1H-carbazole-5-ol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-((1H-indazol-5-yl)oxy)-5 was obtained. -(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (5.0 mg, yield 13%).
1H NMR(400MHz,CDCl 3):δ11.98(br,1H),8.10(d,J=2.3Hz,1H),8.04(s,1H),7.86(dd,J=8.7Hz,2.3Hz,1H),7.53(t,J=6.3Hz,1H),7.40(dd,J=12.1Hz,2.6Hz,2H),7.29(s,1H),7.09(dd,J=8.9Hz,2.2Hz,1H),7.02(t,J=8.7Hz,1H),6.59(d,J=3.4Hz,1H),3.17(q,J=7.4Hz,2H),2.78(s,3H),1.35(t,J=7.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.98 (br, 1H), 8.10 (d, J = 2.3Hz, 1H), 8.04 (s, 1H), 7.86 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.53 (t, J = 6.3 Hz, 1H), 7.40 (dd, J = 12.1 Hz, 2.6 Hz, 2H), 7.29 (s, 1H), 7.09 (dd, J = 8.9 Hz, 2.2 Hz, 1H) ), 7.02 (t, J = 8.7 Hz, 1H), 6.59 (d, J = 3.4 Hz, 1H), 3.17 (q, J = 7.4 Hz, 2H), 2.78 (s, 3H), 1.35 (t, J) =7.4Hz, 3H).
MS m/z(ESI):449.1[M+H] +MS m/z (ESI): 449.1 [M+H] + .
实施例48Example 48
4-(5-(乙基磺酰)-2-((1-甲基环丙基)甲氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(ethylsulfonyl)-2-((1-methylcyclopropyl)methoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000163
Figure PCTCN2018073989-appb-000163
以(1-甲基环丙基)甲醇代替环己醇为原料,参照实施例26第六步,得到化合物4-(5-(乙基磺酰)-2-((1-甲基环丙基)甲氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(15.0mg,产率42%)。Using (1-methylcyclopropyl)methanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, the compound 4-(5-(ethylsulfonyl)-2-((1-methylcyclopropane) was obtained. Methoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (15.0 mg, yield 42%).
1H NMR(400MHz,CD 3OD):δ7.98–7.77(m,2H),7.33(d,J=3.4Hz,1H),7.29–7.15(m,2H),6.37(d,J=3.4Hz,1H),3.84(s,2H),3.14(q,J=7.4Hz,2H),2.62(s,3H),1.16(t,J=7.4Hz,3H),0.89(s,3H),0.37(t,J=5.0Hz,2H),0.20(t,J=5.1Hz,2H). 1 H NMR (400 MHz, CD 3 OD): δ 7.98 - 7.77 (m, 2H), 7.33 (d, J = 3.4 Hz, 1H), 7.29 - 7.15 (m, 2H), 6.37 (d, J = 3.4) Hz, 1H), 3.84 (s, 2H), 3.14 (q, J = 7.4 Hz, 2H), 2.62 (s, 3H), 1.16 (t, J = 7.4 Hz, 3H), 0.89 (s, 3H), 0.37 (t, J = 5.0 Hz, 2H), 0.20 (t, J = 5.1 Hz, 2H).
MS m/z(ESI):401.1[M+H] +MS m/z (ESI): 401.1 [M+H] + .
实施例49Example 49
4-(5-(乙基磺酰)-2-((1-甲基-1H-吲哚-5-基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(ethylsulfonyl)-2-((1-methyl-1H-indol-5-yl)oxy)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000164
Figure PCTCN2018073989-appb-000164
以1-甲基-1H-吲哚-5-酚代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(5-(乙基磺酰)-2-((1-甲基-1H-吲哚-5-基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(10.0mg,产率24%)。Using 1-methyl-1H-indol-5-phenol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(5-(ethylsulfonyl)-2-(( 1-methyl-1H-indol-5-yl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (10.0 mg, yield 24 %).
1H NMR(400MHz,CDCl 3):δ11.38(s,1H),8.08(d,J=2.3Hz,1H),7.77(dd,J=8.8Hz,2.3Hz,1H),7.33–7.29(m,4H),7.12(d,J=3.1Hz,1H),7.01–6.81(m,2H),6.59(d,J=3.4Hz,1H),6.46(d,J=3.0Hz,1H),3.82(s,3H),3.15(q,J=7.4Hz,2H),2.75(s,3H),1.33(t,J=7.4Hz,4H). 1 H NMR (400MHz, CDCl 3 ): δ11.38 (s, 1H), 8.08 (d, J = 2.3Hz, 1H), 7.77 (dd, J = 8.8Hz, 2.3Hz, 1H), 7.33-7.29 ( m, 4H), 7.12 (d, J = 3.1 Hz, 1H), 7.01 - 6.81 (m, 2H), 6.59 (d, J = 3.4 Hz, 1H), 6.46 (d, J = 3.0 Hz, 1H), 3.82 (s, 3H), 3.15 (q, J = 7.4 Hz, 2H), 2.75 (s, 3H), 1.33 (t, J = 7.4 Hz, 4H).
MS m/z(ESI):462.1[M+H] +MS m/z (ESI): 4621. [M+H] + .
实施例50Example 50
4-(2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[ 2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000165
Figure PCTCN2018073989-appb-000165
以1H-吡咯并[2,3-b]吡啶-5-酚代替3-(三氟甲基)苯酚为原料,参照实施例29,得到化合物4-(2-((1H-吡咯并[2,3-b]吡啶-5-基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(12.0mg,产率25%)。Using 1H-pyrrolo[2,3-b]pyridine-5-phenol instead of 3-(trifluoromethyl)phenol as a starting material, referring to Example 29, the compound 4-(2-((1H-pyrrolo[2]] ,3-b]pyridin-5-yl)oxo)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide ( 12.0 mg, yield 25%).
1H NMR(400MHz,CDCl 3):δ12.38(s,1H),10.25(s,1H),8.13(t,J=14.3Hz,2H),7.84(dd,J=8.7Hz,2.3Hz,1H),7.66(d,J=1.5Hz,1H),7.43(d,J=2.6Hz,1H),7.35(d,J=3.2Hz,1H),7.28(s,1H),7.00(d,J=8.7Hz,1H),6.56(d,J=3.3Hz,1H),6.49(d,J=2.7Hz,1H),3.17(q,J=7.4Hz,2H),2.79(s,3H),1.34(t,J=7.4Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.38 (s, 1H), 10.25 (s, 1H), 8.13 (t, J = 14.3Hz, 2H), 7.84 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.66 (d, J = 1.5 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.35 (d, J = 3.2 Hz, 1H), 7.28 (s, 1H), 7.00 (d, J=8.7 Hz, 1H), 6.56 (d, J=3.3 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 3.17 (q, J=7.4 Hz, 2H), 2.79 (s, 3H) , 1.34 (t, J = 7.4 Hz, 3H).
MS m/z(ESI):449.1[M+H] +MS m/z (ESI): 449.1 [M+H] + .
实施例51Example 51
4-(5-(乙基磺酰)-2-((反式)-4-甲基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(ethylsulfonyl)-2-((trans)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide
Figure PCTCN2018073989-appb-000166
Figure PCTCN2018073989-appb-000166
以反-4-甲基环己胺代替环己醇为原料,参照实施例26第六步,得到4-(5-(乙基磺酰)-2-((反式)-4-甲基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.050g,白色固体,产率60%)。Using trans-4-methylcyclohexylamine instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, 4-(5-(ethylsulfonyl)-2-((trans)-4-methyl was obtained. Cyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.050 g, white solid, yield 60%).
MS m/z(ESI):428.2[M+H]+.MS m/z (ESI): 428.2 [M+H]+.
1H NMR(400MHz,CD 3OD):δ12.35(br,1H),7.76(dd,J=8.8Hz,2.4Hz,1H),7.65(d,J=2.0Hz,1H),7.35(d,J=3.2Hz,1H),7.04(s,1H),6.78(d,J=8.8Hz,1H),6.35(d,J=3.2Hz,1H),4.27(d,J=7.2Hz,1H),3.37-3.25(m,1H),3.09(q,J=7.2Hz,2H),2.77(s,3H),2.03-1.90(m,4H),1.74-1.72(m,2H),1.30(t,J=7.2Hz,3H),1.10-0.96(m,3H),0.90(d,J=6.8Hz,3H). 1 H NMR (400MHz, CD 3 OD): δ12.35 (br, 1H), 7.76 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.65 (d, J = 2.0Hz, 1H), 7.35 (d , J = 3.2 Hz, 1H), 7.04 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.35 (d, J = 3.2 Hz, 1H), 4.27 (d, J = 7.2 Hz, 1H) ), 3.37-3.25 (m, 1H), 3.09 (q, J = 7.2 Hz, 2H), 2.77 (s, 3H), 2.03-1.90 (m, 4H), 1.74-1.72 (m, 2H), 1.30 ( t, J = 7.2 Hz, 3H), 1.10-0.96 (m, 3H), 0.90 (d, J = 6.8 Hz, 3H).
实施例52Example 52
4-(2-((反式)-4-(叔丁基)环己基)氧代)-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((trans)-4-(tert-butyl)cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000167
Figure PCTCN2018073989-appb-000167
以反-4-叔丁基环己醇代替环己醇为原料,参照实施例26第六步,得到4-(2-((反式)-4-(叔丁基)环己基)氧代)-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧化(0.040g,白色固体,产率57%)。Using trans-4-tert-butylcyclohexanol instead of cyclohexanol as the starting material, referring to the sixth step of Example 26, 4-(2-((trans)-4-(tert-butyl)cyclohexyl)oxo)- 5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation (0.040 g, white solid, yield 57%).
MS m/z(ESI):471.2[M+H] +. MS m/z (ESI): 471.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ12.63(s,1H),7.97(d,J=2.0Hz 1H),7.89(dd,J=8.4Hz,2.0Hz,1H),7.30(d,J=3.2Hz,1H),7.16(d,J=8.4Hz,1H),7.12(s,1H),6.38(d,J=3.2Hz,1H),4.33-4.22(m,1H),3.15(q,J=7.2Hz,2H),2.77(s,3H),2.16-2.13(m,2H),1.85-1.82(m,2H),1.34-1.25(m,5H),1.16-0.97(m,3H),0.85(s,9H). 1 H NMR (400MHz, CDCl 3 ): δ12.63 (s, 1H), 7.97 (d, J = 2.0Hz 1H), 7.89 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.30 (d, J =3.2 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 7.12 (s, 1H), 6.38 (d, J = 3.2 Hz, 1H), 4.33-4.22 (m, 1H), 3.15 (q) , J=7.2Hz, 2H), 2.77(s,3H), 2.16-2.13(m,2H),1.85-1.82(m,2H),1.34-1.25(m,5H),1.16-0.97(m,3H ), 0.85 (s, 9H).
实施例53Example 53
4-(2-((反式)-4-(乙基)环己基)氧代)-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((trans)-4-(ethyl)cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide
Figure PCTCN2018073989-appb-000168
Figure PCTCN2018073989-appb-000168
第一步:4-(2-((反式)-4-(乙基)环己基)氧代)-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物First step: 4-(2-((trans)-4-(ethyl)cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2 ,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000169
Figure PCTCN2018073989-appb-000169
室温下,将反-4-乙基环己醇(0.077g,0.60mmol)溶解于N,N-二甲基甲酰胺(4mL)中,然后将氢化钠(60%,0.036g,0.90mmol)加入到反应液中,室温搅拌半小时后将4-(2-氟-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.04g,0.12mmol)的N,N-二甲基甲酰胺(1mL)滴加到反应体系中。室温搅拌过夜后,反应液用乙酸乙酯(20mL)稀释,饱和食盐水(20mL)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用反相制备色谱分离得到4-(2-((反式)-4-(乙基)环己基)氧代)-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.030g,白色固体,产率57%)。The trans-4-ethylcyclohexanol (0.077 g, 0.60 mmol) was dissolved in N,N-dimethylformamide (4 mL), then sodium hydride (60%, <RTIgt; After adding to the reaction solution, stirring at room temperature for half an hour, 4-(2-fluoro-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide (0.04 g, 0.12 mmol) of N,N-dimethylformamide (1 mL) was added dropwise to the reaction mixture. After stirring at room temperature overnight, the reaction mixture was diluted w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 2-((trans)-4-(ethyl)cyclohexyl)oxo-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-Oxide (0.030 g, white solid, yield 57%).
MS m/z(ESI):443.2[M+H] +. MS m/z (ESI): 443.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.81(br,1H),7.95(s,1H),7.89(dd,J=8.8Hz,2.0Hz,1H),7.33(d,J=3.2Hz,1H),7.16-7.12(m,2H),6.38(d,J=3.2Hz,1H),4.35-4.25(m,1H),3.13(q,J=7.2Hz,2H),2.76(s,3H),2.10-2.08(m,4H),1.84-1.80(m,2H),1.32(t,J=7.2Hz,3H),1.25-1.16(m,2H),1.14-1.05(m,1H),1.04-0.95(m,2H),0.87(t,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.81 (br, 1H), 7.95 (s, 1H), 7.89 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.33 (d, J = 3.2Hz, 1H), 7.16-7.12 (m, 2H), 6.38 (d, J = 3.2 Hz, 1H), 4.35-4.25 (m, 1H), 3.13 (q, J = 7.2 Hz, 2H), 2.76 (s, 3H) ), 2.10-2.08 (m, 4H), 1.84-1.80 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H), 1.25-1.16 (m, 2H), 1.14-1.05 (m, 1H), 1.04-0.95 (m, 2H), 0.87 (t, J = 7.2 Hz, 3H).
实施例54Example 54
4-(2-((反式)-4-(甲基)环己基)氧代)-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((trans)-4-(methyl)cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide
Figure PCTCN2018073989-appb-000170
Figure PCTCN2018073989-appb-000170
按照实施例53的实验步骤,以反-4-甲基环己醇代替反-4-乙基环己醇为原料,得到4-(2-((反式)-4-(甲基)环己基)氧代)-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧(0.040g,白色固体,产率63%)。Following the experimental procedure of Example 53, substituting trans-4-methylcyclohexanol for trans-4-ethylcyclohexanol as the starting material gave 4-(2-((trans)-4-(methyl)). Hexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxo (0.040 g, white solid, yield 63%).
MS m/z(ESI):429.2[M+H] +. MS m/z (ESI): 429.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ12.13(br,1H),7.96(d,J=2.4Hz,1H),7.90(dd,J=8.4Hz,2.4Hz,1H),7.33(d,J=3.2Hz,1H),7.16-7.13(m,2H),6.40(d,J=3.2Hz,1H),4.35-4.27(m,1H),3.14(q,J=7.6Hz,2H),2.76(s,3H),2.09-2.05(m,2H),1.80-1.74(m,2H),1.39-1.30(m,6H),1.09-0.99(m,2H),0.90(t,J=6.4Hz,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 12.13 (br, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.16-7.13 (m, 2H), 6.40 (d, J = 3.2 Hz, 1H), 4.35-4.27 (m, 1H), 3.14 (q, J = 7.6 Hz, 2H), 2.76(s,3H),2.09-2.05(m,2H),1.80-1.74(m,2H), 1.39-1.30(m,6H), 1.09-0.99(m,2H),0.90(t,J=6.4 Hz, 3H).
实施例55Example 55
4-(2-((反式)-4-(丙基)环己基)氧代)-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((trans)-4-(propyl)cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide
Figure PCTCN2018073989-appb-000171
Figure PCTCN2018073989-appb-000171
按照实施例53的实验步骤,以反-4-丙基环己醇代替反-4-乙基环己醇为原料,得到4-(2-((反式)-4-(丙基)环己基)氧代)-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧(0.030g,白色固体,产率55%)。Following the experimental procedure of Example 53, using trans-4-propylcyclohexanol in place of trans-4-ethylcyclohexanol as the starting material gave 4-(2-((trans))-4-(propyl) ring. Hexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxo (0.030 g, white solid, yield 55%).
MS m/z(ESI):457.2[M+H] +. MS m / z (ESI): 457.2 [M + H] +.
1H NMR(400MHz,CDCl 3):δ11.67(br,1H),7.96(d,J=2.4Hz,1H),7.90(dd,J=8.4Hz,2.4Hz,1H),7.34(d,J=3.6Hz,1H),7.17-7.14(m,2H),6.42(d,J=3.6Hz,1H),4.35-4.27(m,1H),3.15(q,J=7.2Hz,2H),2.76(s,3H),2.10-2.07(m,2H),1.86-1.78(m,2H),1.34-1.28(m,8H),1.23-1.15(m,2H),1.04-0.95(m,2H),0.87(t,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.67 (br, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.90 (dd, J = 8.4Hz, 2.4Hz, 1H), 7.34 (d, J = 3.6 Hz, 1H), 7.17-7.14 (m, 2H), 6.42 (d, J = 3.6 Hz, 1H), 4.35-4.27 (m, 1H), 3.15 (q, J = 7.2 Hz, 2H), 2.76(s,3H), 2.10-2.07(m,2H),1.86-1.78(m,2H),1.34-1.28(m,8H),1.23-1.15(m,2H),1.04-0.95(m,2H ), 0.87 (t, J = 7.2 Hz, 3H).
实施例56Example 56
4-(2-((反式)-4-(异丙基)环己基)氧代)-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((trans)-4-(isopropyl)cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000172
Figure PCTCN2018073989-appb-000172
按照实施例53的实验步骤,以反-4-异丙基环己醇代替反-4-乙基环己醇为原料,得到4-(2-((反式)-4-(异丙基)环己基)氧代)-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧(0.020g,白色固体,产率49%)。Following the experimental procedure of Example 53, substituting trans-4-isopropylcyclohexanol for trans-4-ethylcyclohexanol to give 4-(2-((trans))-4-(isopropyl) Cyclohexyl)oxo)-5-(ethanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxo (0.020 g, white solid, yield 49%) ).
MS m/z(ESI):457.2[M+H] +. MS m / z (ESI): 457.2 [M + H] +.
1H NMR(400MHz,CDCl 3):δ11.70(br,1H),7.96(d,J=2.0Hz,1H),7.90(dd, J=8.8Hz,2.0Hz,1H),7.33(d,J=3.2Hz,1H),7.17-7.14(m,2H),6.42(d,J=3.2Hz,1H),4.35-4.23(m,1H),3.15(q,J=14.8Hz,2H),2.76(s,3H),2.13-2.08(m,2H),1.80-1.77(m,2H),1.51-1.39(m,1H),1.34-1.26(m,5H),1.15-1.06(m,3H),0.87(t,J=6.8Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ11.70 (br, 1H), 7.96 (d, J = 2.0Hz, 1H), 7.90 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.17-7.14 (m, 2H), 6.42 (d, J = 3.2 Hz, 1H), 4.35-4.23 (m, 1H), 3.15 (q, J = 14.8 Hz, 2H), 2.76(s,3H),2.13-2.08(m,2H),1.80-1.77(m,2H),1.51-1.39(m,1H),1.34-1.26(m,5H),1.15-1.06(m,3H ), 0.87 (t, J = 6.8 Hz, 6H).
实施例57Example 57
4-(2-((1H-吲唑-6-基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((1H-carbazol-6-yl)oxo)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000173
Figure PCTCN2018073989-appb-000173
按照实施例53的实验步骤,以1H-吲唑-6-醇代替反-4-乙基环己醇为原料,得到4-(2-((1H-吲唑-6-基)氧代)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物。According to the experimental procedure of Example 53, 1H-carbazole-6-ol was used instead of trans-4-ethylcyclohexanol to obtain 4-(2-((1H-carbazol-6-yl)oxy). 5-(Ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide.
1H NMR(400MHz,CD 3OD):δ8.18(d,J=2.1Hz,1H),8.13(dd,J=8.3Hz,2.1Hz,1H),7.99(s,1H),7.90(d,J=8.3Hz,1H),7.83(s,1H),7.36(d,J=8.7Hz,1H),7.15-7.05(m,1H),6.87(s,1H),6.53(d,J=8.7,1H),6.33(s,1H),6.08-5.98(m,1H),3.34–3.27(m,2H),2.45(s,3H),1.24(t,3H). 1 H NMR (400MHz, CD 3 OD): δ8.18 (d, J = 2.1Hz, 1H), 8.13 (dd, J = 8.3Hz, 2.1Hz, 1H), 7.99 (s, 1H), 7.90 (d , J = 8.3 Hz, 1H), 7.83 (s, 1H), 7.36 (d, J = 8.7 Hz, 1H), 7.15 - 7.05 (m, 1H), 6.87 (s, 1H), 6.53 (d, J = 8.7, 1H), 6.33 (s, 1H), 6.08-5.98 (m, 1H), 3.34 - 3.27 (m, 2H), 2.45 (s, 3H), 1.24 (t, 3H).
MS m/z(ESI):449.1[M+H] + MS m/z (ESI): 449.1 [M+H] +
实施例58Example 58
4-(2-(4-氰基苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-Cyanophenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000174
Figure PCTCN2018073989-appb-000174
按照实施例53的实验步骤,以对羟基苯甲氰代替反-4-乙基环己醇为原料,得到4-(2-(4-氰基苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物。According to the experimental procedure of Example 53, using p-hydroxybenzoic acid instead of trans-4-ethylcyclohexanol as starting material, 4-(2-(4-cyanophenoxy)-5-(ethylsulfonyl) was obtained. Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide.
1H NMR(400MHz,MeOD):δ8.05(d,J=3.7Hz,1H),7.96(d,J=11.8Hz,3.7Hz,1H),7.53–7.45(m,2H),7.33(dd,J=9.5Hz,5.9Hz,2H),7.17(s,1H),6.95–6.86(m,2H),6.42(d,J=3.4Hz,1H),3.27–3.18(m,2H),2.53(s,3H),1.19(t,J=7.4Hz,3H). 1 H NMR (400MHz, MeOD) : δ8.05 (d, J = 3.7Hz, 1H), 7.96 (d, J = 11.8Hz, 3.7Hz, 1H), 7.53-7.45 (m, 2H), 7.33 (dd , J = 9.5 Hz, 5.9 Hz, 2H), 7.17 (s, 1H), 6.95 - 6.86 (m, 2H), 6.42 (d, J = 3.4 Hz, 1H), 3.27 - 3.18 (m, 2H), 2.53 (s, 3H), 1.19 (t, J = 7.4 Hz, 3H).
MS m/z(ESI):434.1[M+H] + MS m/z (ESI): 434.1 [M+H] +
实施例59Example 59
4-(5-(乙基磺酰)-2-(4-(羟甲基)苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化 物4-(5-(ethylsulfonyl)-2-(4-(hydroxymethyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide
Figure PCTCN2018073989-appb-000175
Figure PCTCN2018073989-appb-000175
按照实施例53的实验步骤,以4-(羟甲基)苯酚代替反-4-乙基环己醇为原料,得到4-(5-(乙基磺酰)-2-(4-(羟甲基)苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物。Following the experimental procedure of Example 53, 4-(hydroxymethyl)phenol was used instead of trans-4-ethylcyclohexanol to give 4-(5-(ethylsulfonyl)-2-(4-(hydroxy) Methyl)phenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide.
1H NMR(400MHz,CD 3OD):δ8.11(d,J=2.3Hz,1H),7.97(dd,J=8.7Hz,2.4Hz,1H),7.46(d,J=3.4Hz,1H),7.41–7.35(m,3H),7.20(d,J=8.7Hz,1H),7.02(d,J=8.6Hz,2H),6.60(d,J=3.4Hz,1H),4.58(s,2H),3.33–3.25(m,2H),2.72(s,3H),1.35–1.26(m,3H). 1 H NMR (400 MHz, CD 3 OD): δ 8.11 (d, J = 2.3 Hz, 1H), 7.97 (dd, J = 8.7 Hz, 2.4 Hz, 1H), 7.46 (d, J = 3.4 Hz, 1H) ), 7.41 - 7.35 (m, 3H), 7.20 (d, J = 8.7 Hz, 1H), 7.02 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 3.4 Hz, 1H), 4.58 (s) , 2H), 3.33–3.25 (m, 2H), 2.72 (s, 3H), 1.35–1.26 (m, 3H).
MS m/z(ESI):439.1[M+H] + MS m/z (ESI): 439.1 [M+H] +
实施例60Example 60
4-(2-(环丙基甲氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧化4-(2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation
Figure PCTCN2018073989-appb-000176
Figure PCTCN2018073989-appb-000176
以环丙甲醇代替环己醇为原料,参照实施例26第六步,得到4-(2-(环丙基甲氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化(22.8mg,产率39.4%)。Using cyclopropanol in place of cyclohexanol as a starting material, referring to the sixth step of Example 26, 4-(2-(cyclopropylmethoxy)-5-(ethylsulfonyl)phenyl)-6-methyl was obtained. -1H-pyrrolo[2,3-b]pyridine-7-oxidation (22.8 mg, yield 39.4%).
1H NMR(400MHz,CDCl 3):δ12.75(s,1H),8.02(s,1H),7.99(d,J=2.4Hz,1H),7.56(d,J=2.4Hz,1H),7.35(s,1H),7.20-7.18(d,J=8.4Hz,1H),6.55(d,J=3.2Hz,1H),3.99–3.97(d,J=6.8Hz,2H),3.19-3.13(q,J=7.2Hz,2H),2.93(s,3H),1.34–1.31(t,J=7.2Hz,3H),1.18-1.16(m,1H),0.62–0.60(m,2H),0.31–0.29(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ12.75 (s, 1H), 8.02 (s, 1H), 7.99 (d, J = 2.4Hz, 1H), 7.56 (d, J = 2.4Hz, 1H), 7.35(s,1H), 7.20-7.18 (d, J=8.4Hz, 1H), 6.55 (d, J=3.2Hz, 1H), 3.99–3.97 (d, J=6.8Hz, 2H), 3.19-3.13 (q, J = 7.2 Hz, 2H), 2.93 (s, 3H), 1.34 - 1.31 (t, J = 7.2 Hz, 3H), 1.18-1.16 (m, 1H), 0.62 - 0.60 (m, 2H), 0.31–0.29 (m, 2H).
MS m/z(ESI):387.1[M+H] +MS m/z (ESI): 387.1 [M+H] + .
实施例61Example 61
4-(2-(4-(2-氨基-2-羰基乙基)苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-(2-Amino-2-carbonylethyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000177
Figure PCTCN2018073989-appb-000177
按照实施例53的实验步骤,以2-(4-羟苯基)乙酰胺代替反-4-乙基环己醇为原料,得到4-(2-(4-(2-氨基-2-羰基乙基)苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物。Following the experimental procedure of Example 53, 2-(4-hydroxyphenyl)acetamide was used instead of trans-4-ethylcyclohexanol to give 4-(2-(4-(2-amino-2-carbonyl) Ethyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide.
1H NMR(400MHz,CD 3OD):δ8.12(d,J=2.3Hz,1H),7.99(dd,J=8.8Hz,2.3Hz,1H),7.55(d,J=3.4Hz,1H),7.48(s,1H),7.34(d,J=8.6Hz,2H),7.23(d,J=8.7Hz,1H),7.03(d,J=8.6Hz,2H),6.68(d,J=3.4Hz,1H),3.51(s,2H),3.34–3.27(m,2H),2.77(s,3H),1.30(t,J=7.4Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ 8.12 (d, J = 2.3 Hz, 1H), 7.99 (dd, J = 8.8 Hz, 2.3 Hz, 1H), 7.55 (d, J = 3.4 Hz, 1H) ), 7.48 (s, 1H), 7.34 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 8.6 Hz, 2H), 6.68 (d, J) = 3.4 Hz, 1H), 3.51 (s, 2H), 3.34 - 3.27 (m, 2H), 2.77 (s, 3H), 1.30 (t, J = 7.4 Hz, 3H).
MS m/z(ESI):466.1[M+H] + MS m/z (ESI): 466.1 [M+H] +
实施例62Example 62
6-甲基-4-(2-((反式)-4-乙基环己基)氨基)-5-(乙磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000178
Figure PCTCN2018073989-appb-000178
第一步:N-(4-乙基环己基)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(乙磺酰)苯胺First step: N-(4-ethylcyclohexyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(ethanesulfonyl)aniline
Figure PCTCN2018073989-appb-000179
Figure PCTCN2018073989-appb-000179
在10毫升微波管中加入4-(2-氟-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.025g,0.075mmol),4-乙基环己胺(0.3mL)和N-甲基吡咯烷酮(3mL),在油浴中加热至140℃,反应过夜,冷却至室温。反应液用乙酸乙酯(20mL)稀释,盐水洗涤,有机相用无水硫酸钠干燥,过滤,旋干,得粗产物N-(4-乙基环己基)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(乙磺酰)苯胺(0.050g,黄色油状物)。粗品直接用于下一步反应。Add 4-(2-fluoro-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.025 g) to a 10 mL microwave tube , 0.075 mmol), 4-ethylcyclohexylamine (0.3 mL) and N-methylpyrrolidone (3 mL) were heated to 140 ° C in an oil bath and allowed to react overnight and cooled to room temperature. The reaction mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. 1H-Pyrolo[2,3-b]pyridin-4-yl)-4-(ethanesulfonyl)aniline (0.050 g, yellow oil). The crude product was used directly in the next reaction.
MS m/z(ESI):426.2[M+H] +MS m/z (ESI): 426.2 [M+H] + .
第二步:6-甲基-4-(2-((反式)-4-乙基环己基)氨基)-5-(乙磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物The second step: 6-methyl-4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000180
Figure PCTCN2018073989-appb-000180
将粗产物N-(4-乙基环己基)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(乙磺酰)苯胺(0.050g,黄色油状物)溶解于二氯甲烷中(10mL),然后将间氯过氧苯甲酸(85%,0.055g,0.27mmol)加入到反应液中,室温搅拌。反应结束后,反应液用二氯甲烷(20mL)稀释,饱和碳酸氢钠溶液洗涤,盐水洗涤,无水硫酸钠干燥,过滤,旋干,粗产物用反相制备色谱分离得到6-甲基-4-(2-((反式)-4-乙基环己基)氨基)-5-(乙磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.008g,白色固体,产率15%)。The crude product N-(4-ethylcyclohexyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(ethanesulfonyl)aniline (0.050 g, yellow oil) was dissolved in dichloromethane (10 mL), then m-chloroperoxybenzoic acid (85%, 0.055 g, 0.27 mmol) was added to the reaction mixture and stirred at room temperature. After completion of the reaction, the reaction mixture was diluted with methylene chloride (20 mL), washed with NaHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 4-(2-((trans)-4-ethylcyclohexyl)amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide ( 0.008 g, white solid, yield 15%).
MS m/z(ESI):442.2[M+H] +. MS m / z (ESI): 442.2 [M + H] +.
1H NMR(400MHz,CDCl 3):δ12.26(br,1H),7.78(d,J=8.8Hz 1H),7.66(s,1H),7.40(s,1H),7.07(s,1H),6.79(d,J=8.8Hz,1H),6.37(d,J=3.2Hz,1H),4.29(d,J=8.0Hz,1H),3.32(br,1H),3.11(q,J=7.2Hz,2H),2.78(s,3H),2.05(br,2H),1.86-1.73(br,2H),1.31(t,J=7.2Hz,3H),1.24-1.18(m,2H),1.15-0.93(m,5H),0.87(t,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.26 (br, 1H), 7.78 (d, J = 8.8Hz 1H), 7.66 (s, 1H), 7.40 (s, 1H), 7.07 (s, 1H) , 6.79 (d, J = 8.8 Hz, 1H), 6.37 (d, J = 3.2 Hz, 1H), 4.29 (d, J = 8.0 Hz, 1H), 3.32 (br, 1H), 3.11 (q, J = 7.2 Hz, 2H), 2.78 (s, 3H), 2.05 (br, 2H), 1.86-1.73 (br, 2H), 1.31 (t, J = 7.2 Hz, 3H), 1.24-1.18 (m, 2H), 1.15-0.93 (m, 5H), 0.87 (t, J = 7.2 Hz, 3H).
实施例63Example 63
6-甲基-4-(5-(乙磺酰)-2-(((反式)-4-丙基环己基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(5-(ethanesulfonyl)-2-(((trans)-4-propylcyclohexyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine -7-oxide
Figure PCTCN2018073989-appb-000181
Figure PCTCN2018073989-appb-000181
按照实施例62的实验步骤,以4-丙基环己胺代替4-乙基环己胺为原料,得到6-甲基-4-(2-((反式)-4-丙基环己基)氨基)-5-(乙磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.015g,白色固体,产率23%)。Following the experimental procedure of Example 62, 4-propylcyclohexylamine was used instead of 4-ethylcyclohexylamine to give 6-methyl-4-(2-((trans)-4-propylcyclohexyl). Amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.015 g, white solid, yield 23%).
MS m/z(ESI):456.2[M+H] +. MS m/z (ESI): 456.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ12.25(br,1H),7.76(dd,J=8.8Hz,2.0Hz,1H),7.66(d,J=2.0Hz,1H),7.43(d,J=3.2Hz,1H),7.09(s,1H),6.81(d,J=8.8Hz,1H),6.39(d,J=3.2Hz,1H),4.30(d,J=7.2Hz,1H),3.31(br,1H),3.10(q,J=7.2Hz,2H),2.79(s,3H),2.05(br,2H),1.80-1.78(m,2H),1.32-1.29(m,5H),1.20-1.17(m,3H),1.04-1.00(m,4H),0.87(t,J=7.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.25 (br, 1H), 7.76 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.66 (d, J = 2.0Hz, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.09 (s, 1H), 6.81 (d, J = 8.8 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 4.30 (d, J = 7.2 Hz, 1H) , 3.31 (br, 1H), 3.10 (q, J = 7.2 Hz, 2H), 2.79 (s, 3H), 2.05 (br, 2H), 1.80-1.78 (m, 2H), 1.32-1.29 (m, 5H) ), 1.20-1.17 (m, 3H), 1.04-1.00 (m, 4H), 0.87 (t, J = 7.6 Hz, 3H).
实施例64Example 64
6-甲基-4-(5-(乙磺酰)-2-(((顺式)-4-丙基环己基)氨基)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(5-(ethanesulfonyl)-2-(((cis)-4-propylcyclohexyl)amino)phenyl)-1H-pyrrolo[2,3-b]pyridine -7-oxide
Figure PCTCN2018073989-appb-000182
Figure PCTCN2018073989-appb-000182
按照实施例62的实验步骤,以4-丙基环己胺代替4-乙基环己胺为原料,得到6-甲基-4-(2-((顺式)-4-丙基环己基)氨基)-5-(乙磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.010g,白色固体,产率15%)。Following the experimental procedure of Example 62, 4-propylcyclohexylamine was used instead of 4-ethylcyclohexylamine to give 6-methyl-4-(2-((cis)-4-propylcyclohexyl). Amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.010 g, white solid, yield 15%).
MS m/z(ESI):456.2[M+H] +. MS m/z (ESI): 456.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.92(br,1H),7.76(d,J=9.2Hz,1H),7.69(s,1H),7.43(s,1H),7.11(s,1H),6.80(d,J=9.2Hz,1H),6.47(d,J=2.8Hz,1H),4.53(d,J=6.4Hz,1H),3.65(br,1H),3.11(q,J=7.2Hz,2H),2.79(s,3H),1.64-1.49(m,6H),1.33-1.22(m,6H),1.14-1.08(m,2H),1.01-0.90(m,2H),0.86(t,J=7.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.92 (br, 1H), 7.76 (d, J = 9.2Hz, 1H), 7.69 (s, 1H), 7.43 (s, 1H), 7.11 (s, 1H ), 6.80 (d, J = 9.2 Hz, 1H), 6.47 (d, J = 2.8 Hz, 1H), 4.53 (d, J = 6.4 Hz, 1H), 3.65 (br, 1H), 3.11 (q, J) = 7.2 Hz, 2H), 2.79 (s, 3H), 1.64-1.49 (m, 6H), 1.33-1.22 (m, 6H), 1.14-1.08 (m, 2H), 1.01-0.90 (m, 2H), 0.86 (t, J = 7.6 Hz, 3H).
实施例65Example 65
6-甲基-4-(2-((顺式)-4-乙基环己基)氨基)-5-(乙磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(2-((cis)-4-ethylcyclohexyl)amino)-5-(ethanesulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000183
Figure PCTCN2018073989-appb-000183
参照实施例62的实验步骤,制备分离同时得到6-甲基-4-(2-((顺式)-4-乙基环己基)氨基)-5-(乙磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.008g,白色固体,产率24%)。Referring to the experimental procedure of Example 62, the separation was carried out to obtain 6-methyl-4-(2-((cis)-4-ethylcyclohexyl)amino)-5-(ethanesulfonyl)phenyl)-1H. Pyrrolo[2,3-b]pyridine-7-oxide (0.008 g, white solid, yield 24%).
MS m/z(ESI):442.2[M+H] +. MS m / z (ESI): 442.2 [M + H] +.
1H NMR(400MHz,CDCl 3):δ11.96(s,1H),7.76(dd,J=8.8Hz,2.0Hz,1H),7.69(d,J=2.0Hz 1H),7.33(d,J=3.2Hz,1H),7.07(s,1H),6.78(d,J=8.8Hz,1H),6.41(d,J=3.2Hz,1H),4.56(d,J=6.4Hz,1H),3.65(br,1H),3.10(q,J=7.2Hz,2H),2.78(s,3H),1.72-1.51(m,6H),1.31(t,J=7.2Hz,3H),1.19-1.12(m,3H),0.98-0.85(m,2H),0.82(t,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.96 (s, 1H), 7.76 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.69 (d, J = 2.0Hz 1H), 7.33 (d, J =3.2 Hz, 1H), 7.07 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 3.2 Hz, 1H), 4.56 (d, J = 6.4 Hz, 1H), 3.65 (br, 1H), 3.10 (q, J = 7.2 Hz, 2H), 2.78 (s, 3H), 1.72-1.51 (m, 6H), 1.31 (t, J = 7.2 Hz, 3H), 1.19-1.12 (m, 3H), 0.98-0.85 (m, 2H), 0.82 (t, J = 7.2 Hz, 3H).
实施例66Example 66
4-(2-(4-(氨基甲基)苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-(Aminomethyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide
Figure PCTCN2018073989-appb-000184
Figure PCTCN2018073989-appb-000184
第一步:4-(2-(4-(((叔-丁氧基羰基)氨基)甲基)苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物First step: 4-(2-(4-((tert-butoxycarbonyl)amino)methyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H -pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000185
Figure PCTCN2018073989-appb-000185
室温下,将叔丁基(4-羟基苄基)氨基甲酸酯(0.050g,0.224mmol)溶解于N,N-二甲基甲酰胺(2mL)中,然后将氢化钠(60%,0.012g,0.30mmol)加入到反应液中,室温搅拌半小时。然后将4-(2-氟-5-(乙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.05g,0.24mmol)的N,N-二甲基甲酰胺(1mL)滴加到反应体系中,加热至80℃反应五小时。反应结束后,反应液用乙酸乙酯(20mL)稀释,饱和食盐水(10mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用制备板(石油醚:乙酸乙酯=1:1,V/V)分离得到(0.030g,无色油状物,产率37%)。tert-Butyl (4-hydroxybenzyl)carbamate (0.050 g, 0.224 mmol) was dissolved in N,N-dimethylformamide (2 mL), then sodium hydride (60%, 0.012) g, 0.30 mmol) was added to the reaction mixture, and stirred at room temperature for half an hour. 4-(2-Fluoro-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.05 g, 0.24 mmol) N,N-dimethylformamide (1 mL) was added dropwise to the reaction system, and heated to 80 ° C for five hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (20 mL), and brine (10 mL×2) was evaporated. Ester = 1:1, V/V) isolated (0.030 g, colourless oil, yield 37%).
MS m/z(ESI):538.2[M+H] +. MS m/z (ESI): 538.2 [M+H] + .
第二步:4-(2-(4-(氨基甲基)苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物Second step: 4-(2-(4-(aminomethyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Pyridine-7-oxide
Figure PCTCN2018073989-appb-000186
Figure PCTCN2018073989-appb-000186
室温下,将4-(2-(4-(((叔丁氧基羰基)氨基)甲基)苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(30mg,0.056mmol)溶解于二氯甲烷(2mL),然后将三氟乙酸(0.5mL)滴加到反应液中,反应两小时后,将反应液蒸干,残留物用乙酸乙酯(20mL)溶解,有机相用饱和碳酸氢钠溶液(10mL)洗涤, 饱和食盐水(10mL)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用反相制备色谱分离得到4-(2-(4-(氨基甲基)苯氧基)-5-(乙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(12mg,灰色固体,产率49%)。4-(2-(4-(((tert-Butyloxy)))amino)methyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H- Pyrrolo[2,3-b]pyridine-7-oxide (30 mg, 0.056 mmol) was dissolved in dichloromethane (2 mL), then trifluoroacetic acid (0.5 mL) was added dropwise to the reaction mixture for two hours. The reaction mixture was evaporated to dryness. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Spin-drying, the crude product was isolated by reverse phase preparative chromatography to give 4-(2-(4-(aminomethyl)phenoxy)-5-(ethylsulfonyl)phenyl)-6-methyl-1H-pyrrole And [2,3-b]pyridine-7-oxide (12 mg, gray solid, yield 49%).
MS m/z(ESI):438.1[M+H] +. MS m/z (ESI): 438.1 [M+H] + .
1H NMR(400MHz,CD 3OD):δ8.39(br,1H),8.02(d,J=2.4Hz,1H),7.90(dd,J=8.8Hz,2.4Hz,1H),7.34(d,J=3.6Hz,1H),7.28(d,J=8.4Hz,2H),7.22(s,1H),7.18(d,J=8.4Hz,1H),6.91(d,J=8.8Hz,2H),6.46(d,J=3.2Hz,1H),4.50(br,2H),3.94(s,2H),3.19(q,J=7.2Hz,2H),2.56(s,3H),1.19(t,J=7.2Hz,3H). 1 H NMR (400 MHz, CD 3 OD): δ 8.39 (br, 1H), 8.02 (d, J = 2.4 Hz, 1H), 7.90 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.34 (d) , J = 3.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.22 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H) ), 6.46 (d, J = 3.2 Hz, 1H), 4.50 (br, 2H), 3.94 (s, 2H), 3.19 (q, J = 7.2 Hz, 2H), 2.56 (s, 3H), 1.19 (t) , J = 7.2 Hz, 3H).
实施例67Example 67
4-(2-(2,4-二氟苯氧基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(2,4-Difluorophenoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-A keto-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000187
Figure PCTCN2018073989-appb-000187
第一步:S-(3-溴-4-氟苯基)乙硫酸酯的制备First step: Preparation of S-(3-bromo-4-fluorophenyl)ethyl sulfate
Figure PCTCN2018073989-appb-000188
Figure PCTCN2018073989-appb-000188
将2-溴-1-氟-4-碘苯(8.8g,29.3mmol),硫代乙酸钾(4.7g,41.1mmol),碘化亚铜(557mg,2.93mmol),1,10-菲啰啉(1.05g,5.86mmol)溶于甲苯(100mL),置换氮气,加热到100℃搅拌过夜,LC/MS检测反应完全。向反应液中加入水(100mL),用乙酸乙酯(150mL)萃取,有机相用饱和食盐水(100mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=10:1,V/V)得S-(3-溴-4-氟苯基)乙硫酸酯(5.5g,产率75%)。2-Bromo-1-fluoro-4-iodobenzene (8.8 g, 29.3 mmol), potassium thioacetate (4.7 g, 41.1 mmol), cuprous iodide (557 mg, 2.93 mmol), 1,10-phenanthrenequinone The porphyrin (1.05 g, 5.86 mmol) was dissolved in toluene (100 mL), and the mixture was replaced with nitrogen and heated to 100 ° C overnight. The reaction was completed by LC/MS. Water (100 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (150 mL). Ethyl ester = 10:1, V/V) gave S-(3-bromo-4-fluorophenyl)ethylsulfate (5.5 g, yield 75%).
1H NMR(400MHz,DMSO-d 6):δ7.81–7.79(m,1H),7.50–7.48(m,2H),2.45(s,3H)。 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.81 - 7.79 (m, 1H), 7.50 - 7.48 (m, 2H), 2.45 (s, 3H).
第二步:(3-溴-4-氟苯基)(2,2,2-三氟乙基)硫烷的制备Second step: Preparation of (3-bromo-4-fluorophenyl)(2,2,2-trifluoroethyl)sulfane
Figure PCTCN2018073989-appb-000189
Figure PCTCN2018073989-appb-000189
将S-(3-溴-4-氟苯基)乙硫酸酯(5.0g,16.9mmol)溶于乙腈/甲醇(20mL/20mL)混合溶剂,加入碳酸铯(19.6g,60mmol),搅拌5分钟后,加入2-溴-1,1,1-三氟乙烷(8.4g,40mmol),室温下反应过夜。向反应液中加入水(100mL),用乙酸乙酯(100mL)萃取,有机相用饱和食盐水(100mL)洗涤,用无水硫酸钠干燥,浓 缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=10:1,V/V)得(3-溴-4-氟苯基)(2,2,2-三氟乙基)硫烷(3.0g,产率52.0%)。S-(3-Bromo-4-fluorophenyl)ethylsulfate (5.0 g, 16.9 mmol) was dissolved in acetonitrile / methanol (20 mL / 20 mL) mixed solvent, cesium carbonate (19.6 g, 60 mmol) was added and stirred for 5 min. Thereafter, 2-bromo-1,1,1-trifluoroethane (8.4 g, 40 mmol) was added, and the mixture was reacted at room temperature overnight. Water (100 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (100 mL). Ethyl ester = 10:1, V/V) gave (3-bromo-4-fluorophenyl)(2,2,2-trifluoroethyl)sulfane (3.0 g, yield 52.0%).
1H NMR(400MHz,CDCl 3):δ7.74–7.72(m,1H),7.47–7.43(m,1H),7.11-7.05(m,1H),3.42-3.35(q,J=9.6Hz,2H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.74 - 7.72 (m, 1H), 7.47 - 7.43 (m, 1H), 7.11 - 7.05 (m, 1H), 3.42-3.35 (q, J = 9.6 Hz, 2H).
第三步:2-溴-1-氟-4-((2,2,2-三氟乙基)磺酰)苯的制备The third step: preparation of 2-bromo-1-fluoro-4-((2,2,2-trifluoroethyl)sulfonyl)benzene
Figure PCTCN2018073989-appb-000190
Figure PCTCN2018073989-appb-000190
将(3-溴-4-氟苯基)(2,2,2-三氟乙基)硫烷(3.0g,16.9mmol)溶于二氯甲烷(40mL),加入间氯过氧苯甲酸(5.36g,3.12mmol),室温搅拌2小时。向反应液中加入饱乙酸乙酯(100mL),用饱和碳酸钠溶液(50mL×2)洗涤,然后用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=10:1,V/V)得2-溴-1-氟-4-((2,2,2-三氟乙基)磺酰)苯(2.1g,产率63%).(3-Bromo-4-fluorophenyl)(2,2,2-trifluoroethyl)sulfane (3.0 g, 16.9 mmol) was dissolved in dichloromethane (40 mL) and m-chloroperoxybenzoic acid ( 5.36 g, 3.12 mmol), stirred at room temperature for 2 hours. Ethyl acetate (100 mL) was added to the mixture, and the mixture was washed with saturated aqueous sodium sulfate (50 mL×2) (petroleum ether: ethyl acetate = 10:1, V/V) gave 2-bromo-1-fluoro-4-((2,2,2-trifluoroethyl)sulfonyl)benzene (2.1 g, yield 63%).
1H NMR(400MHz,CDCl 3):δ8.21–8.19(m,1H),7.96–7.92(m,1H),7.37-7.33(m,1H),3.97-3.90(q,J=8.8Hz,2H)。 1 H NMR (400MHz, CDCl 3 ): δ8.21-8.19 (m, 1H), 7.96-7.92 (m, 1H), 7.37-7.33 (m, 1H), 3.97-3.90 (q, J = 8.8Hz, 2H).
第四步:2-溴-1-氟-4-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯的制备Fourth step: Preparation of 2-bromo-1-fluoro-4-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)benzene
Figure PCTCN2018073989-appb-000191
Figure PCTCN2018073989-appb-000191
将2-溴-1-氟-4-((2,2,2-三氟乙基)磺酰)苯(600mg,1.94mmol)溶于四氢呋喃/六甲基磷酰三胺(10mL/8mL),加入碘甲烷(5mL),用干冰/丙酮浴冷却至-78℃,加入二异丙基氨基锂四氢呋喃溶液(2M,2.4mL,4.8mmol),在-78℃下搅拌30分钟,然后升温至-50℃搅拌20分钟。然后向反应液中加入饱和氯化铵溶液(50mL)淬灭反应。用乙酸乙酯(100mL)萃取,有机相用饱和食盐水(100mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=10:1,V/V)得2-溴-1-氟-4-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯(300mg,产率46%)。 1H NMR(400MHz,CDCl 3):δ8.15–8.13(m,1H),7.90–7.86(m,1H),7.34-7.30(m,1H),1.61(s,6H)。 2-Bromo-1-fluoro-4-((2,2,2-trifluoroethyl)sulfonyl)benzene (600 mg, 1.94 mmol) was dissolved in tetrahydrofuran / hexamethylphosphoric acid triamine (10 mL / 8 mL) Add iodomethane (5 mL), cool to -78 ° C with dry ice / acetone bath, add diisopropylamino lithium tetrahydrofuran solution (2M, 2.4 mL, 4.8 mmol), stir at -78 ° C for 30 min, then warm to Stir at -50 ° C for 20 minutes. Then, a saturated ammonium chloride solution (50 mL) was added to the reaction mixture to quench the reaction. The mixture was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. 2-Bromo-1-fluoro-4-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)benzene (300 mg, yield 46%). 1 H NMR (400MHz, CDCl 3 ): δ8.15-8.13 (m, 1H), 7.90-7.86 (m, 1H), 7.34-7.30 (m, 1H), 1.61 (s, 6H).
第五步:4-(2-氟-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备Step 5: 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1-toluene Preparation of acyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000192
Figure PCTCN2018073989-appb-000192
将2-溴-1-氟-4-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯(930mg,2.66mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(1.6g,2.93mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(39mg,0.05mmol),碳酸钾(0.74g,5.32mmol)溶于1,4-二氧六环(32mL)和水(8mL)的混合溶剂,置换氮气,加热到100℃搅拌过夜,LC/MS检测反应完全。向反应液中加入水(100mL),用乙酸乙酯(100mL)萃取,有机相用饱和食盐水(100mL)洗涤,后用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=2:1,V/V)得4-(2-氟-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(0.88g,产率60.0%)。2-Bromo-1-fluoro-4-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)benzene (930 mg, 2.66 mmol), 6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.6 g, 2.93 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (39 mg, 0.05 mmol), potassium carbonate (0.74 g, 5.32 mmol) dissolved in 1,4- A mixed solvent of dioxane (32 mL) and water (8 mL) was replaced with nitrogen, heated to 100 ° C overnight, and the reaction was completed by LC/MS. Water (100 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (100 mL). Ethyl acetate = 2:1, V/V) gave 4-(2-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)- 6-Methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (0.88 g, yield 60.0%).
MS m/z(ESI)=555.1[M+H] + MS m/z (ESI) = 555.1 [M+H] +
第六步:4-(2-氟-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Step 6: 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine
Figure PCTCN2018073989-appb-000193
Figure PCTCN2018073989-appb-000193
将4-(2-氟-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(880mg,1.59mmol)溶于叔丁醇(30mL),将氢氧化钾水溶液(3M,15mL)加入上述溶液中,加热到70℃搅拌过夜。冷却至室温后向反应液中加乙酸乙酯(80mL)稀释,然后用饱和食盐水(100mL)洗涤,无水硫酸钠干燥,浓缩得4-(2-氟-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(400mg,产率63.0%).4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H - Pyrrolo[2,3-b]pyridine (880 mg, 1.59 mmol) was dissolved in tert-butanol (30 mL), and aqueous potassium hydroxide (3M, 15 mL) was added to the above solution and heated to 70 ° C overnight. After cooling to room temperature, it was diluted with ethyl acetate (80 mL), and then washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and evaporated to give 4-(2-fluoro-5-((1,1, 1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (400 mg, yield 63.0%).
MS m/z(ESI):401.1[M+H] + MS m/z (ESI): 401.1 [M+H] +
第七步:4-(2-氟-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 7: 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000194
Figure PCTCN2018073989-appb-000194
将4-(2-氟-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(400mg,1.0mmol)溶于四氢呋喃(10mL),加入间氯过氧苯甲酸(304mg,1.5mmol),室温搅拌20分钟后LC/MS检测反应完全。向反应液中加入饱乙酸乙酯(60mL),用饱和碳酸钠溶液(50mL×2)洗涤,然后用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,浓缩得4-(2-氟-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯 基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧化(320mg,产率77.0%)。4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine (400 mg, 1.0 mmol) was dissolved in tetrahydrofuran (10 mL). m. m. Ethyl acetate (60 mL) was added to the reaction mixture, which was washed with saturated aqueous sodium sulfate (50 mL×2), then washed with brine (50 mL) 5-((1,1,1-Trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation (320 mg, yield 77.0%).
MS m/z(ESI):416.1[M+H] + MS m/z (ESI): 416.1 [M+H] +
第八步:4-(2-(2,4-二氟苯氧基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 8: 4-(2-(2,4-Difluorophenoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl) Preparation of -6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000195
Figure PCTCN2018073989-appb-000195
将4-(2-氟-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化(120mg,0.29mmol)溶于N-甲基吡咯烷酮(3mL),加入2,4-二氟苯酚(150mg,1.15mmol),碳酸铯(375mg,1.15mmol),微波条件下加热到180℃反应30分钟。冷却至室温后向反应液中加乙酸乙酯(50mL),然后用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶制备板分离纯化(二氯甲烷:甲醇=10:1,V/V)得4-(2-(2,4-二氟苯氧基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(30.0mg,产率20%).4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine-7-oxidation (120 mg, 0.29 mmol) was dissolved in N-methylpyrrolidone (3 mL), 2,4-difluorophenol (150 mg, 1.15 mmol), cesium carbonate (375 mg, 1.15 mmol), The reaction was heated to 180 ° C for 30 minutes under microwave conditions. After cooling to room temperature, ethyl acetate (50 mL) was added, and the mixture was washed with brine (50 mL). 1,V/V) gives 4-(2-(2,4-difluorophenoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl) Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (30.0 mg, yield 20%).
1H NMR(400MHz,CDCl 3):δ11.85(s,1H),8.07(s,1H),7.90-7.87(d,J=8.8Hz,1H),7.52(s,1H),7.26–7.23(m,1H),7.15-7.09(m,1H),7.04-6.99(m,1H),6.96-6.92(m,2H),6.56(s,1H),2.60(s,3H),1.64(s,6H)。 1 H NMR (400MHz, CDCl 3 ): δ11.85 (s, 1H), 8.07 (s, 1H), 7.90-7.87 (d, J = 8.8Hz, 1H), 7.52 (s, 1H), 7.26-7.23 (m, 1H), 7.15-7.09 (m, 1H), 7.04-6.99 (m, 1H), 6.96-6.92 (m, 2H), 6.56 (s, 1H), 2.60 (s, 3H), 1.64 (s) , 6H).
MS m/z(ESI):527.0[M+H] + MS m/z (ESI): 527.0 [M+H] +
实施例68Example 68
4-(2-(4-溴-2-氟苯氧基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-Bromo-2-fluorophenoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6- Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000196
Figure PCTCN2018073989-appb-000196
按照实施例67第八步的实验步骤,以4-溴-2-氟苯酚代替2,4-二氟苯酚为原料,得4-(2-(4-溴-2-氟苯氧基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(16.5mg,产率23.4%).According to the experimental procedure of the eighth step of Example 67, 4-bromo-2-fluorophenol was used instead of 2,4-difluorophenol to obtain 4-(2-(4-bromo-2-fluorophenoxy)- 5-((1,1,1-Trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide (16.5mg, yield 23.4%).
1H NMR(400MHz,CDCl 3):δ12.35(s,1H),8.11(s,1H),7.89-7.86(m,1H),7.41–7.35(m,2H),7.32-7.28(m,1H),7.21(s,1H),7.01-6.94(m,2H),6.49(s,1H),2.77(s,3H),1.62(s,6H). 1 H NMR (400MHz, CDCl 3 ): δ12.35 (s, 1H), 8.11 (s, 1H), 7.89-7.86 (m, 1H), 7.41-7.35 (m, 2H), 7.32-7.28 (m, 1H), 7.21 (s, 1H), 7.01-6.94 (m, 2H), 6.49 (s, 1H), 2.77 (s, 3H), 1.62 (s, 6H).
MS m/z(ESI):587.0[M+H] + MS m/z (ESI): 587.0 [M+H] +
实施例69Example 69
4-(2-(4-环丙基苯氧基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-Cyclopropylphenoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl -1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000197
Figure PCTCN2018073989-appb-000197
按照实施例67第八步的实验步骤,以4-环丙基苯酚代替2,4-二氟苯酚为原料,得4-(2-(4-环丙基苯氧基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化(19.0mg,产率21%).Following the experimental procedure of the eighth step of Example 67, 4-(4-cyclopropylphenoxy)-5-(( 1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxidation (19.0 mg , yield 21%).
1H NMR(400MHz,CDCl 3):δ11.60(s,1H),8.07(s,1H),7.83-7.81(d,J=8.0Hz,1H),7.36(s,1H),7.21(s,1H),7.10–7.08(d,J=8.4Hz,2H),7.02–7.00(d,J=8.8Hz,1H),6.94–6.92(d,J=8.8Hz,2H),6.50(s,1H),2.75(s,3H),1.92–1.88(m,1H),1.63(s,6H),1.00–0.96(m,2H),0.69–0.65(m,2H)。 1 H NMR (400MHz, CDCl 3 ): δ11.60 (s, 1H), 8.07 (s, 1H), 7.83-7.81 (d, J = 8.0Hz, 1H), 7.36 (s, 1H), 7.21 (s , 1H), 7.10–7.08 (d, J=8.4Hz, 2H), 7.02–7.00 (d, J=8.8Hz, 1H), 6.94–6.92 (d, J=8.8Hz, 2H), 6.50(s, 1H), 2.75 (s, 3H), 1.92 - 1.88 (m, 1H), 1.63 (s, 6H), 1.00 - 0.96 (m, 2H), 0.69 - 0.65 (m, 2H).
MS m/z(ESI):531.0[M+H] + MS m/z (ESI): 531.0 [M+H] +
实施例70Example 70
6-甲基-4-(2-(吡啶-4-氧基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(2-(pyridin-4-yloxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-1H -pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000198
Figure PCTCN2018073989-appb-000198
按照实施例67第八步的实验步骤,以4-羟基吡啶代替2,4-二氟苯酚为原料,得6-甲基-4-(2-(吡啶-4-氧基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(17.5mg,产率21%).According to the experimental procedure of the eighth step of Example 67, 4-hydroxypyridine was used instead of 2,4-difluorophenol to obtain 6-methyl-4-(2-(pyridin-4-yloxy)-5-( (1,1,1-Trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (17.5 mg, yield twenty one%).
1H NMR(400MHz,CDCl 3):δ12.42(s,1H),8.18-8.12(m,2H),7.70-7.68(d,J=8.4Hz,1H),7.35-7.34(d,J=3.2Hz,1H),7.28–7.26(m,2H),6.75(s,1H),6.27–6.25(d,J=7.2Hz,2H),6.21–6.20(d,J=3.2Hz,1H),2.68(s,3H),1.69(s,6H)。 1 H NMR (400 MHz, CDCl 3 ): δ 12.42 (s, 1H), 8.18-8.12 (m, 2H), 7.70-7.68 (d, J = 8.4 Hz, 1H), 7.35-7.34 (d, J = 3.2 Hz, 1H), 7.28–7.26 (m, 2H), 6.75 (s, 1H), 6.27–6.25 (d, J=7.2 Hz, 2H), 6.21–6.20 (d, J=3.2 Hz, 1H), 2.68 (s, 3H), 1.69 (s, 6H).
MS m/z(ESI):492.1[M+H] + MS m/z (ESI): 492.1 [M+H] +
实施例71Example 71
6-甲基-4-(2-(((反式)-4-甲基环己基)氧代)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(2-((trans)-4-methylcyclohexyl)oxo)-5-((1,1,1-trifluoro-2-methylpropan-2-yl) Sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000199
Figure PCTCN2018073989-appb-000199
将(反式)-4-甲基-环己醇(178mg,1.56mmol)溶于N-甲基吡咯烷酮(2mL),加入氢化钠(63.0mg,1.56mmol),室温下搅拌10分钟,将4-(2-氟-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧化(65mg,0.16mmol)加入上述反应液中,室温下反应5小时,LCMS检测反应完全。向反应液中加乙酸乙酯(50mL),然后用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,,浓缩后用反相制备色谱分离纯化(C 18柱,流动相(乙腈/水)得6-甲基-4-(2-(((反式)-4-甲基环己基)氧代)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(15.0mg,产率19%). (trans)-4-methyl-cyclohexanol (178 mg, 1.56 mmol) was dissolved in N-methylpyrrolidone (2 mL), sodium hydride (63.0 mg, 1.56 mmol) was added and stirred at room temperature for 10 min, 4 -(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b] Pyridine 7-oxidation (65 mg, 0.16 mmol) was added to the above reaction mixture, and the mixture was reacted at room temperature for 5 hours, and the reaction was confirmed by LCMS. The reaction mixture was added ethyl acetate (50mL), then with saturated brine (50mL), dried over anhydrous sodium sulfate ,, and concentrated Purification by reverse phase preparative chromatography (C 18 column, mobile phase (acetonitrile / water To give 6-methyl-4-(2-((trans)-4-methylcyclohexyl)oxo)-5-((1,1,1-trifluoro-2-methylpropane-2) -yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (15.0 mg, yield 19%).
1H NMR(400MHz,CDCl 3):δ11.76(s,1H),7.97(d,J=2.4Hz,1H),7.93-7.90(dd,J=8.8Hz,2.4Hz,1H),7.35(d,J=3.2Hz,1H),7.16–7.13(m,2H),6.41(d,J=3.6Hz,1H),4.36–4.31(m,1H),2.76(s,3H),2.09–2.07(t,J=5.6Hz,2H),1.78–1.75(m,2H),1.62(s,6H),1.40–1.30(m,3H),1.10–1.00(m,2H),0.92-0.90(d,J=6.4Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ): δ 11.76 (s, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.93 - 7.90 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.35 ( d, J = 3.2 Hz, 1H), 7.16 - 7.13 (m, 2H), 6.41 (d, J = 3.6 Hz, 1H), 4.36 - 4.31 (m, 1H), 2.76 (s, 3H), 2.09 - 2.07 (t, J = 5.6 Hz, 2H), 1.78 - 1.75 (m, 2H), 1.62 (s, 6H), 1.40 - 1.30 (m, 3H), 1.10 - 1.00 (m, 2H), 0.92 - 0.90 (d , J = 6.4 Hz, 3H).
MS m/z(ESI):511.1[M+H] + MS m/z (ESI): 511.1 [M+H] +
实施例72Example 72
4-(2-(((反式)-4-羟基环己基)氧代)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备4-(2-(((trans)-4-hydroxycyclohexyl)oxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl Preparation of 6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000200
Figure PCTCN2018073989-appb-000200
将反式-1,4-环己二醇(100mg,0.86mmol)溶于N-甲基吡咯烷酮(2mL),加入氢化钠(40.0mg,5.2mmol),室温下搅拌10分钟,将4-(2-氟-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧化(80mg,0.19mmol)加入上述反应液中,加热40℃反应过夜,LCMS检测反应完全。向反应液中加乙酸乙酯(50mL),然后用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶制备板分离纯化(二氯甲烷:甲醇=10:1,V/V)得4-(2-(((反式)-4-羟基环己基)氧代)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(27.5mg,产率28%).The trans-1,4-cyclohexanediol (100 mg, 0.86 mmol) was dissolved in N-methylpyrrolidone (2 mL), sodium hydride (40.0 mg, 5.2 mmol) was added, and stirred at room temperature for 10 minutes, 4-( 2-fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Pyridine 7-oxidation (80 mg, 0.19 mmol) was added to the above reaction mixture, and the mixture was heated at 40 ° C overnight, and the reaction was completed by LCMS. Ethyl acetate (50 mL) was added to the mixture, and the mixture was washed with brine (50 mL) V) gives 4-(2-((trans)-4-hydroxycyclohexyl)oxo)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (27.5 mg, yield 28%).
1H NMR(400MHz,CDCl 3):δ12.30(s,1H),7.97(d,J=2.4Hz,1H),7.94-7.91 (dd,J=8.8Hz,2.4Hz,1H),7.32(d,J=3.2Hz,1H),7.17–7.14(m,2H),6.39(d,J=3.2Hz,1H),4.53–4.49(m,1H),3.76–3.66(m,2H),2.78(s,3H),2.12–2.05(m,2H),2.00–1.97(m,2H),1.84–1.80(m,2H),1.62(s,6H),1.60–1.45(m,2H)。 1 H NMR (400 MHz, CDCl 3 ): δ 12.30 (s, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.94 - 7.91 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.32 ( d, J = 3.2 Hz, 1H), 7.17 - 7.14 (m, 2H), 6.39 (d, J = 3.2 Hz, 1H), 4.53 - 4.49 (m, 1H), 3.76 - 3.66 (m, 2H), 2.78 (s, 3H), 2.12 - 2.05 (m, 2H), 2.00 - 1.97 (m, 2H), 1.84 - 1.80 (m, 2H), 1.62 (s, 6H), 1.60 - 1.45 (m, 2H).
MS m/z(ESI):513.1[M+H] + MS m/z (ESI): 513.1 [M+H] +
实施例73Example 73
4-(2-(环丙基甲氧基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(cyclopropylmethoxy)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H -pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000201
Figure PCTCN2018073989-appb-000201
参照实施例71,用环丙基甲醇取代(反式)-4-甲基-环己醇,得4-(2-(环丙基甲氧基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(15.5mg,产率48.5%).Refer to Example 71, substituting (trans)-4-methyl-cyclohexanol with cyclopropylmethanol to give 4-(2-(cyclopropylmethoxy)-5-((1,1,1- Trifluoro-2-methylpropan-2-ylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (15.5 mg, yield 48.5%) ).
1H NMR(400MHz,CDCl 3):δ12.56(s,1H),8.00(d,J=2.4Hz,1H),7.94-7.91(dd,J=8.8Hz,2.0Hz,1H),7.35(d,J=3.2Hz,1H),7.18(s,1H),7.13–7.11(d,J=8.8Hz,1H),6.41(d,J=3.2Hz,1H),3.97(d,J=6.8Hz,2H),2.79(s,3H),1.62(s,6H),1.19–1.13(m,1H),0.60–0.56(m,2H),0.31-0.28(m,2H)。 1 H NMR (400 MHz, CDCl 3 ): δ 12.56 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.94 - 7.91 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.35 ( d, J = 3.2 Hz, 1H), 7.18 (s, 1H), 7.13 - 7.11 (d, J = 8.8 Hz, 1H), 6.41 (d, J = 3.2 Hz, 1H), 3.97 (d, J = 6.8) Hz, 2H), 2.79 (s, 3H), 1.62 (s, 6H), 1.19 - 1.13 (m, 1H), 0.60 - 0.56 (m, 2H), 0.31 - 0.28 (m, 2H).
MS m/z(ESI):469.1[M+H] + MS m/z (ESI): 469.1 [M+H] +
实施例74Example 74
4-(2-((4,4-二氟环己基)氧代)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((4,4-Difluorocyclohexyl)oxo)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)- 6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000202
Figure PCTCN2018073989-appb-000202
参照实施例71,用4,4-二氟环己醇取代(反式)-4-甲基-环己醇,得4-(2-((4,4-二氟环己基)氧代)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(11.0mg,产率42.5%).Referring to Example 71, substituting 4,4-difluorocyclohexanol for (trans)-4-methyl-cyclohexanol gave 4-(2-((4,4-difluorocyclohexyl)oxo) -5-((1,1,1-Trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 - Oxide (11.0 mg, yield 42.5%).
1H NMR(400MHz,CDCl 3):δ12.19(s,1H),8.01(d,J=2.4Hz,1H),7.96-7.93(dd,J=8.8Hz,2.0Hz,1H),7.34(d,J=3.2Hz,1H),7.17–7.15(d,J=8.8Hz,1H),7.10(s,1H),6.39(d,J=3.2Hz,1H),4.72-4.64(m,1H),2.83(s,3H),2.13–1.70(m,8H),1.63(s,6H)。 1 H NMR (400 MHz, CDCl 3 ): δ 12.19 (s, 1H), 8.1 (d, J = 2.4 Hz, 1H), 7.96-7.93 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.34 ( d, J = 3.2 Hz, 1H), 7.17 - 7.15 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 6.39 (d, J = 3.2 Hz, 1H), 4.72-4.64 (m, 1H) ), 2.83 (s, 3H), 2.13 - 1.70 (m, 8H), 1.63 (s, 6H).
MS m/z(ESI):533.1[M+H] + MS m/z (ESI): 533.1 [M+H] +
实施例75Example 75
6-甲基-4-(2-(((反式)-4-甲基环己基)氨基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Methyl-4-(2-(((trans)-4-methylcyclohexyl)amino)-5-((1,1,1-trifluoro-2-methylpropan-2-yl)) Sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000203
Figure PCTCN2018073989-appb-000203
将4-(2-氟-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(70mg,0.17mmol)和(反式)-4-甲基-环己胺(190mg,1.68mmol)溶于N-甲基吡咯烷酮(2mL),加N,N-二异丙基乙胺(0.5mL),加热到120℃搅拌过夜。冷却至室温后向反应液中加乙酸乙酯(50mL),然后用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,浓缩后用反相制备色谱分离纯化(C 18柱,流动相(乙腈/水))得6-甲基-4-(2-(((反式)-4-甲基环己基)氨基)-5-((1,1,1-三氟-2-甲基丙烷-2-基)磺酰)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(12.0mg,产率14.7%). 4-(2-Fluoro-5-((1,1,1-trifluoro-2-methylpropan-2-yl)sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine-7-oxide (70 mg, 0.17 mmol) and (trans)-4-methyl-cyclohexylamine (190 mg, 1.68 mmol) were dissolved in N-methylpyrrolidone (2 mL). N-Diisopropylethylamine (0.5 mL) was heated to 120 ° C and stirred overnight. After cooling to room temperature, ethyl acetate (50 mL) was added, and then washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated and purified by reverse phase preparative chromatography ( C18 column, mobile phase ( Acetonitrile/water)) gives 6-methyl-4-(2-((trans)-4-methylcyclohexyl)amino)-5-((1,1,1-trifluoro-2-methyl) Propane-2-yl)sulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (12.0 mg, yield 14.7%).
1H NMR(400MHz,CDCl 3):δ12.62(s,1H),7.77-7.74(dd,J=8.8Hz,1.6Hz,1H),7.66(s,1H),7.36(d,J=2.0Hz,1H),7.03(s,1H),7.79–7.77(d,J=9.2Hz,1H),6.32(d,J=2.8Hz,1H),4.39–4.37(d,J=7.2Hz,1H),3.37-3.30(m,1H),2.79(s,3H),2.05–1.93(m,2H),1.75–1.64(m,2H),1.59(s,6H),1.32–1.25(m,3H),1.10–0.91(m,2H),0.88-0.86(d,J=7.2Hz,3H)。 1 H NMR (400MHz, CDCl 3 ): δ12.62 (s, 1H), 7.77-7.74 (dd, J = 8.8Hz, 1.6Hz, 1H), 7.66 (s, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.03 (s, 1H), 7.79 - 7.77 (d, J = 9.2 Hz, 1H), 6.32 (d, J = 2.8 Hz, 1H), 4.39 - 4.37 (d, J = 7.2 Hz, 1H) ), 3.37-3.30 (m, 1H), 2.79 (s, 3H), 2.05–1.93 (m, 2H), 1.75–1.64 (m, 2H), 1.59 (s, 6H), 1.32–1.25 (m, 3H) ), 1.10 - 0.91 (m, 2H), 0.88 - 0.86 (d, J = 7.2 Hz, 3H).
MS m/z(ESI):510.2[M+H] + MS m/z (ESI): 510.2 [M+H] +
实施例76Example 76
4-(5-(异丙基磺酰)-2-(((反式)-4-甲基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(isopropylsulfonyl)-2-(((trans)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000204
Figure PCTCN2018073989-appb-000204
第一步:(3-溴-4-氟苯基)(异丙基)硫烷的制备First step: Preparation of (3-bromo-4-fluorophenyl)(isopropyl)sulfane
Figure PCTCN2018073989-appb-000205
Figure PCTCN2018073989-appb-000205
将S-(3-溴-4-氟苯基)乙硫酸酯(3.5g,14.1mmol)溶于乙腈/甲醇(20mL/20mL)混合溶剂,加入碳酸铯(13.8g,43.2mmol),搅拌5分钟后,加入2-碘-丙烷(23.8g,141mmol),室温下反应过夜后向反应液中加入水(80mL),用乙酸乙酯(100mL) 萃取,有机相用饱和食盐水(80mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=10:1,V/V)得(3-溴-4-氟苯基)(异丙基)硫烷(3.2g,产率91.0%)。S-(3-Bromo-4-fluorophenyl)ethylsulfate (3.5 g, 14.1 mmol) was dissolved in acetonitrile / methanol (20 mL / 20 mL) mixed solvent, cesium carbonate (13.8 g, 43.2 mmol) was added and stirred 5 After a few minutes, 2-iodo-propane (23.8 g, 141 mmol) was added, and the mixture was stirred at room temperature overnight. Water (80 mL) was evaporated. Drying with anhydrous sodium sulfate, concentrating and purifying by silica gel column chromatography (petrole ether: ethyl acetate = 10:1, V/V) to give (3-bromo-4-fluorophenyl)(isopropyl)sulfide Alkane (3.2 g, yield 91.0%).
MS m/z(ESI):249.0[M+H] + MS m/z (ESI): 249.0 [M+H] +
第二步:(3-溴-4-氟苯基)(异丙基)硫烷的制备Second step: Preparation of (3-bromo-4-fluorophenyl)(isopropyl)sulfane
Figure PCTCN2018073989-appb-000206
Figure PCTCN2018073989-appb-000206
将(3-溴-4-氟苯基)(异丙基)硫烷(3.2g,12.9mmol)溶于二氯甲烷(50mL),加入间氯过氧苯甲酸(7.8g,38.6mmol),室温搅拌3小时后向反应液中加入饱乙酸乙酯(100mL),用饱和碳酸钠溶液(50mL×2)洗涤,然后用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=10:1,V/V)得(3-溴-4-氟苯基)(异丙基)硫烷(2.1g,产率58%).(3-Bromo-4-fluorophenyl)(isopropyl)sulfane (3.2 g, 12.9 mmol) was dissolved in dichloromethane (50 mL) and m-chloroperoxybenzoic acid (7.8 g, 38.6 mmol). After stirring for 3 hours at room temperature, ethyl acetate (100 mL) was added, and the mixture was washed with saturated aqueous sodium carbonate (50 mL×2), then washed with brine (50 mL) Separation and purification by silica gel column chromatography (petrole ether: ethyl acetate = 10:1, V/V) afforded (3-bromo-4-fluorophenyl)(isopropyl)sulfane (2.1 g, yield: 58%).
1H NMR(400MHz,CDCl 3):δ8.13–8.10(m,1H),7.86–7.82(m,1H),7.34-7.27(m,1H),3.24-3.18(m,1H),1.31(d,J=6.8Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ): δ 8.13 - 8.10 (m, 1H), 7.86 - 7.82 (m, 1H), 7.34 - 7.27 (m, 1H), 3.24 - 3.18 (m, 1H), 1.31 ( d, J = 6.8 Hz, 6H).
第三步:4-(2-氟-5-(异丙基磺酰)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备Third step: Preparation of 4-(2-fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000207
Figure PCTCN2018073989-appb-000207
将(3-溴-4-氟苯基)(异丙基)硫烷(1.00g,3.56mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(1.76g,2.93mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(32mg,0.18mmol),碳酸钾(1.47g,10.68mmol)溶于1,4-二氧六环(30mL)和水(10mL)的混合溶剂中,置换氮气,加热到100℃搅拌4小时,LC/MS检测反应完全。向反应液中加入水(100mL),用乙酸乙酯(100mL)萃取,有机相用饱和食盐水(100mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=2:1,V/V)得4-(2-氟-5-(异丙基磺酰)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(0.70g,产率40%)。(3-Bromo-4-fluorophenyl)(isopropyl)sulfane (1.00 g, 3.56 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.76 g, 2.93 mmol), [1,1'-bis(diphenyl) a phosphinyl) ferrocene] palladium dichloride (32 mg, 0.18 mmol), potassium carbonate (1.47 g, 10.68 mmol) dissolved in a mixed solvent of 1,4-dioxane (30 mL) and water (10 mL) The nitrogen gas was replaced, heated to 100 ° C and stirred for 4 hours, and the reaction was confirmed by LC/MS. Water (100 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (100 mL). Ethyl ester = 2:1, V/V) gave 4-(2-fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2, 3-b]pyridine (0.70 g, yield 40%).
MS m/z(ESI):487.1[M+H] + MS m/z (ESI): 487.1 [M+H] +
第四步:4-(2-氟-5-(异丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Fourth step: Preparation of 4-(2-fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000208
Figure PCTCN2018073989-appb-000208
将4-(2-氟-5-(异丙基磺酰)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(700mg,1.44mmol)溶于叔丁醇(30mL),将氢氧化钾溶液(3M,15mL)加入上述溶液中,加热到70℃搅拌过夜。冷却至室温后向反应液中加乙酸乙酯(60mL),有机相用饱和食盐水(50mL×2)洗涤,用无水硫酸钠干燥,浓缩得4-(2-氟-5-(异丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(450mg,产率94%)。4-(2-Fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (700 mg, 1.44 mmol) Dissolved in tert-butanol (30 mL), potassium hydroxide solution (3M, 15 mL) was added to the above solution, and the mixture was stirred at 70 ° C overnight. After cooling to room temperature, ethyl acetate (60 mL) was added, and the organic layer was washed with brine (50 mL×2). Sulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (450 mg, yield 94%).
MS m/z(ESI):333.1[M+H] + MS m/z (ESI): 333.1 [M+H] +
第五步:4-(2-氟-5-(异丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧化的制备Step 5: Preparation of 4-(2-fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation
Figure PCTCN2018073989-appb-000209
Figure PCTCN2018073989-appb-000209
将4-(2-氟-5-(异丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(450mg,1.36mmol)溶于四氢呋喃(5mL),加入间氯过氧苯甲酸(411mg,2.03mmol),室温搅拌1小时,LC/MS检测反应完全。向反应液中加入饱乙酸乙酯(80mL),用饱和碳酸钠溶液(50mL×2)洗涤,然后用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,浓缩得4-(2-氟-5-(异丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧化(400mg,产率85%).4-(2-Fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (450 mg, 1.36 mmol) was dissolved in tetrahydrofuran (5 mL) m-Chloroperoxybenzoic acid (411 mg, 2.03 mmol) was added, and the mixture was stirred at room temperature for 1 hour, and the reaction was confirmed by LC/MS. Ethyl acetate (80 mL) was added to the mixture, and the mixture was washed with saturated sodium sulfate (50 mL×2) -5-(Isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation (400 mg, yield 85%).
MS m/z(ESI):348.1[M+H] + MS m/z (ESI): 348.1 [M+H] +
第六步:4-(5-(异丙基磺酰)-2-(((反式)-4-甲基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧化的制备Step 6: 4-(5-(Isopropylsulfonyl)-2-(((trans)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[ Preparation of 2,3-b]pyridine 7-oxidation
Figure PCTCN2018073989-appb-000210
Figure PCTCN2018073989-appb-000210
将反式-4-甲基环己醇(200mg,1.77mmol)溶于N-甲基吡咯烷酮(2mL),加入氢化钠(100mg,2.5mmol),室温下搅拌10分钟,将4-(2-氟-5-(异丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧化(70mg,0.20mmol)加入上述反应液中,室温下反应3小时,LCMS检测反应完全。向反应液中加乙酸乙酯(50mL),有机相用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,浓缩后用反相制备色谱 分离纯化(C 18柱,流动相(乙腈/水))得4-(5-(异丙基磺酰)-2-(((反式)-4-甲基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(21.0mg,产率24%). Trans-4-methylcyclohexanol (200 mg, 1.77 mmol) was dissolved in N-methylpyrrolidone (2 mL), sodium hydride (100 mg, 2.5 mmol) was added and stirred at room temperature for 10 min, 4-(2- Fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxidation (70 mg, 0.20 mmol) was added to the above reaction solution, and reacted at room temperature. After 3 hours, the LCMS assay was complete. To the reaction solution was added ethyl acetate (50mL), the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by reverse phase preparative chromatography (C 18 column, mobile phase (acetonitrile / water )) 4-(5-(isopropylsulfonyl)-2-(((trans)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2] , 3-b]pyridine-7-oxide (21.0 mg, yield 24%).
1H NMR(400MHz,CDCl 3):δ12.08(s,1H),7.94(d,J=2.4Hz,1H),7.88-7.86(dd,J=8.8Hz,2.4Hz,1H),7.32(d,J=3.2Hz,1H),7.16–7.13(m,2H),6.40(d,J=3.2Hz,1H),4.34–4.28(m,1H),3.24–3.17(m,1H),2.76(s,3H),2.08–2.01(m,2H),1.77–1.74(m,2H),1.39–1.25(m,9H),1.09–1.02(m,2H),0.91-0.90(d,J=6.4Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ): δ 12.08 (s, 1H), 7.94 (d, J = 2.4 Hz, 1H), 7.88-7.86 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.32 ( d, J = 3.2 Hz, 1H), 7.16 - 7.13 (m, 2H), 6.40 (d, J = 3.2 Hz, 1H), 4.34 - 4.28 (m, 1H), 3.24 - 3.17 (m, 1H), 2.76 (s, 3H), 2.08–2.01 (m, 2H), 1.77–1.74 (m, 2H), 1.39–1.25 (m, 9H), 1.09–1.02 (m, 2H), 0.91-0.90 (d, J= 6.4 Hz, 3H).
MS m/z(ESI):443.1[M+H] + MS m/z (ESI): 443.1 [M+H] +
实施例77Example 77
4-(2-(((反式)-4-乙基环己基)氧代)-5-(异丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(((trans)-4-ethylcyclohexyl)oxy)-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000211
Figure PCTCN2018073989-appb-000211
参照实施例76第六步,用(反式)-4-乙基-环己醇取代(反式)-4-甲基-环己醇,得4-(2-(((反式)-4-乙基环己基)氧代)-5-(异丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(14.0mg,产率25.5%).Referring to the sixth step of Example 76, substituting (trans)-4-ethyl-cyclohexanol for (trans)-4-methyl-cyclohexanol gives 4-(2-((trans))- 4-ethylcyclohexyl)oxo)-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (14.0 mg, Yield 25.5%).
1H NMR(400MHz,CDCl 3):δ12.09(s,1H),7.94(d,J=2.4Hz,1H),7.89-7.86(dd,J=8.8Hz,2.4Hz,1H),7.34(d,J=3.6Hz,1H),7.16–7.14(m,2H),6.41(d,J=3.2Hz,1H),4.34–4.29(m,1H),3.24–3.17(m,1H),2.76(s,3H),2.25–2.17(m,2H),1.84–1.81(m,2H),1.37–1.32(m,8H),1.28–1.22(m,3H),1.05–0.99(m,2H),0.89-0.85(t,J=7.2Hz,3H)。 1 H NMR (400MHz, CDCl 3 ): δ12.09 (s, 1H), 7.94 (d, J = 2.4Hz, 1H), 7.89-7.86 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.34 ( d, J = 3.6 Hz, 1H), 7.16 - 7.14 (m, 2H), 6.41 (d, J = 3.2 Hz, 1H), 4.34 - 4.29 (m, 1H), 3.24 - 3.17 (m, 1H), 2.76 (s, 3H), 2.25–2.17 (m, 2H), 1.84–1.81 (m, 2H), 1.37–1.32 (m, 8H), 1.28–1.22 (m, 3H), 1.05–0.99 (m, 2H) , 0.89-0.85 (t, J = 7.2 Hz, 3H).
MS m/z(ESI):457.2[M+H] + MS m/z (ESI): 457.2 [M+H] +
实施例78Example 78
4-(5-(异丙基磺酰)-2-(((反式)-4-丙基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(isopropylsulfonyl)-2-(((trans)-4-propylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000212
Figure PCTCN2018073989-appb-000212
参照实施例76第六步,以4-(2-氟-5-(异丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物为原料,用(反式)-4-丙基-环己醇取代(反式)-4-甲基-环己醇,得4-(5-(异丙基磺酰)-2-(((反式)-4-丙基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(11.0mg,产率21.5%).Referring to the sixth step of Example 76, 4-(2-fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxidation The material is used as a starting material, and (trans)-4-methyl-cyclohexanol is substituted with (trans)-4-propyl-cyclohexanol to give 4-(5-(isopropylsulfonyl)-2-( ((trans)-4-propylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (11.0 mg, yield 21.5%) ).
1H NMR(400MHz,CDCl 3):δ12.34(s,1H),7.95(d,J=2.4Hz,1H),7.88-7.85(dd,J 1=8.8Hz,J 2=2.4Hz,1H),7.31(d,J=3.6Hz,1H),7.16–7.13(m,2H),6.39(d,J=3.2Hz,1H),4.33–4.28(m,1H),3.24–3.17(m,1H),2.76(s,3H),2.10–2.00(m,2H),1.82–1.79(m,2H),1.37–1.20(m,11H),1.19–1.14(m,2H),1.05–0.99(m,2H),0.89-0.85(t,J=7.2Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ): δ 12.34 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.88-7.85 (dd, J 1 = 8.8 Hz, J 2 = 2.4 Hz, 1H ), 7.31 (d, J = 3.6 Hz, 1H), 7.16 - 7.13 (m, 2H), 6.39 (d, J = 3.2 Hz, 1H), 4.33 - 4.28 (m, 1H), 3.24 - 3.17 (m, 1H), 2.76 (s, 3H), 2.10–2.00 (m, 2H), 1.82–1.79 (m, 2H), 1.37–1.20 (m, 11H), 1.19–1.14 (m, 2H), 1.05–0.99 ( m, 2H), 0.89-0.85 (t, J = 7.2 Hz, 3H).
MS m/z(ESI):471.2[M+H] + MS m/z (ESI): 471.2 [M+H] +
实施例79Example 79
4-(2-(((反式)-4-异丙基环己基)氧代)-5-(异丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(((trans)-4-isopropylcyclohexyl)oxy)-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000213
Figure PCTCN2018073989-appb-000213
参照实施例76第六步,用(反式)-4-异丙基-环己醇取代(反式)-4-甲基-环己醇,得4-(2-(((反式)-4-异丙基环己基)氧代)-5-(异丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(16.6mg,产率28.0%).Referring to the sixth step of Example 76, substituting (trans)-4-isopropyl-cyclohexanol for (trans)-4-methyl-cyclohexanol gives 4-(2-((trans)) 4-isopropylcyclohexyl)oxo)-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (16.6 Mg, yield 28.0%).
1H NMR(400MHz,CDCl 3):δ11.84(s,1H),7.95(d,J=2.4Hz,1H),7.89-7.86(dd,J=8.8Hz,2.4Hz,1H),7.36(d,J=3.6Hz,1H),7.17–7.14(m,2H),6.43(d,J=3.2Hz,1H),4.31–4.27(m,1H),3.23–3.19(m,1H),2.76(s,3H),2.14–2.11(m,2H),1.80–1.78(m,2H),1.46–1.43(m,1H),1.35–1.26(m,8H),1.12–1.06(m,3H),0.87-0.85(d,J=6.4Hz,6H)。 1 H NMR (400MHz, CDCl 3 ): δ11.84 (s, 1H), 7.95 (d, J = 2.4Hz, 1H), 7.89-7.86 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.36 ( d, J = 3.6 Hz, 1H), 7.17 - 7.14 (m, 2H), 6.43 (d, J = 3.2 Hz, 1H), 4.31 - 4.27 (m, 1H), 3.23 - 3.19 (m, 1H), 2.76 (s, 3H), 2.14–2.11 (m, 2H), 1.80–1.78 (m, 2H), 1.46–1.43 (m, 1H), 1.35–1.26 (m, 8H), 1.12–1.06 (m, 3H) , 0.87-0.85 (d, J = 6.4 Hz, 6H).
MS m/z(ESI):471.2[M+H] + MS m/z (ESI): 471.2 [M+H] +
实施例80Example 80
4-(5-(异丙基磺酰)-2-(((反式)-4-甲基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(isopropylsulfonyl)-2-(((trans)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide
Figure PCTCN2018073989-appb-000214
Figure PCTCN2018073989-appb-000214
将4-(2-氟-5-(异丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(80mg,0.24mmol)和(反式)-4-甲基-环己胺(1mL)溶于N-甲基吡咯烷酮(2mL),加热到140℃搅拌5小时。向反应液中加乙酸乙酯(50mL),有机相用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,浓缩后用反相制备色谱分离纯化(C 18柱,流动相(乙腈/水))得4-(5-(异丙基磺酰)-2-(((反式)-4-甲基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(16.5mg,产率16%)。 4-(2-Fluoro-5-(isopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (80 mg, 0.24 mmol) and (trans)-4-methyl-cyclohexylamine (1 mL) was dissolved in N-methylpyrrolidone (2 mL), and stirred at 140 ° C for 5 hours. To the reaction solution was added ethyl acetate (50mL), the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by reverse phase preparative chromatography (C 18 column, mobile phase (acetonitrile / water )) 4-(5-(isopropylsulfonyl)-2-(((trans)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine-7-oxide (16.5 mg, yield 16%).
1H NMR(400MHz,CDCl 3):δ12.45(s,1H),7.75-7.72(dd,J=8.8Hz,2.4Hz,1H),7.64(d,J=2.4Hz,1H),7.06(s,1H),6.80-6.78(d,J=8.8Hz,1H),6.36(d,J=3.2Hz,1H),4.28(d,J=8.0Hz,1H),3.32–3.28(m,1H),3.20–3.13(m,1H),2.78(s,3H),2.04–2.00(m,2H),1.75–1.72(m,2H),1.32–1.30(m,7H)1.11–0.96(m,4H),0.91(d,J=6.4Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ): δ 12.45 (s, 1H), 7.75-7.72 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 7.06 ( s, 1H), 6.80-6.78 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 3.2 Hz, 1H), 4.28 (d, J = 8.0 Hz, 1H), 3.32 - 3.28 (m, 1H) ), 3.20–3.13 (m, 1H), 2.78 (s, 3H), 2.04–2.00 (m, 2H), 1.75–1.72 (m, 2H), 1.32–1.30 (m, 7H) 1.11–0.96 (m, 4H), 0.91 (d, J = 6.4 Hz, 3H).
MS m/z(ESI):442.1[M+H] + MS m/z (ESI): 442.1 [M+H] +
实施例81Example 81
4-(5-(环丙基磺酰)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7- Oxide
Figure PCTCN2018073989-appb-000215
Figure PCTCN2018073989-appb-000215
第一步:1,2-二(3-溴-4-氟苯基)二硫烷的制备.The first step: the preparation of 1,2-bis(3-bromo-4-fluorophenyl)disulfane.
Figure PCTCN2018073989-appb-000216
Figure PCTCN2018073989-appb-000216
3L三口瓶中依次加入3-溴-4-氟苯胺(60g,315.6mmol),乙腈(600mL),水(600mL),浓盐酸(300mL)。冰浴冷却至0-5℃,滴加亚硝酸钠(23.4g,316mmol)的水(300mL)溶液,维持体系温度在0-5℃。反应1小时后加入尿素(3.6g,60mmol)淬灭多余的亚硝酸钠,搅拌10分钟。1L的三口瓶中依次加入九水硫化钠(100.8g,420mmol),硫磺粉(13.2g,420mmol),NaOH(17.4g,432mmol),水(300mL)。油浴加热至75℃反应1小时至溶液变澄清。将澄清溶液冷却至室温滴加到上述反应液中,并维持体系温度为0-5℃。滴加完毕后,反应液用乙酸乙酯(1L×2)萃取,过滤,无水硫酸钠干燥,旋干得到粗品1,2-二(3-溴-4-氟苯基)二硫烷(42g,黄色油状物,产率64%)。3-Bromo-4-fluoroaniline (60 g, 315.6 mmol), acetonitrile (600 mL), water (600 mL), and concentrated hydrochloric acid (300 mL). The mixture was cooled to 0-5 ° C in an ice bath, and a solution of sodium nitrite (23.4 g, 316 mmol) in water (300 mL) was added dropwise, maintaining the system temperature at 0-5 °C. After 1 hour of reaction, urea (3.6 g, 60 mmol) was added to quench excess sodium nitrite and stirred for 10 minutes. Sodium sulfide nonahydrate (100.8 g, 420 mmol), sulfur powder (13.2 g, 420 mmol), NaOH (17.4 g, 432 mmol), water (300 mL) were sequentially added to a 1 L three-necked flask. The oil bath was heated to 75 ° C for 1 hour until the solution became clear. The clear solution was cooled to room temperature and added dropwise to the above reaction liquid, and the temperature of the system was maintained at 0 to 5 °C. After completion of the dropwise addition, the reaction mixture was extracted with ethyl acetate (1L×2), filtered, dried over anhydrous sodium sulfate and evaporated to give the crude (1,2-bis(3-bromo-4-fluorophenyl)disulfane ( 42 g, yellow oil, yield 64%).
第二步:3-溴-4-氟苯硫醇的制备The second step: the preparation of 3-bromo-4-fluorobenzenethiol
Figure PCTCN2018073989-appb-000217
Figure PCTCN2018073989-appb-000217
3L三口瓶中依次加入1,2-二(3-溴-4-氟苯基)二硫烷(42g,101.9mmol),甲醇(300mL),四氢呋喃(1L),氢氧化钠(10.3g,257.5mmol)的水(300mL)溶液。室温下分五批加入硼氢化钠(11.1g,293.6mmol)。反应1小时后浓缩,加入氢氧化钠(35g,875.0mmol)的水(300mL)溶液,用甲基叔丁基醚(500mL×2)洗。水相滴加到盐酸(800mL,3mol/L)中,并维持体系温度为 0-5℃。反应液用甲基叔丁基醚(500mL×3)萃取,无水硫酸钠干燥,旋干得到3-溴-4-氟苯硫醇(16g,黄色油状物,产率38%)。1,2-bis(3-bromo-4-fluorophenyl)disulfane (42 g, 101.9 mmol), methanol (300 mL), tetrahydrofuran (1 L), sodium hydroxide (10.3 g, 257.5) were sequentially added to a 3L three-necked flask. A solution of mmol (300 mL) of water. Sodium borohydride (11.1 g, 293.6 mmol) was added in five portions at room temperature. After 1 hour of reaction, the mixture was concentrated. EtOAc EtOAc m. The aqueous phase was added dropwise to hydrochloric acid (800 mL, 3 mol/L) and the system temperature was maintained at 0-5 °C. The reaction mixture was extracted with EtOAc (EtOAc)EtOAc.
1H NMR(400MHz,CDCl 3):δ7.50(dd,J=6.3Hz,2.3Hz,1H),7.23–7.16(m,1H),7.00(t,J=8.4Hz,1H),3.48(s,1H). 1 H NMR (400MHz, CDCl 3 ): δ7.50 (dd, J = 6.3Hz, 2.3Hz, 1H), 7.23-7.16 (m, 1H), 7.00 (t, J = 8.4Hz, 1H), 3.48 ( s, 1H).
第三步:1,2-二(3-溴-4-氟苯基)二硫烷的制备.The third step: the preparation of 1,2-bis(3-bromo-4-fluorophenyl)disulfane.
Figure PCTCN2018073989-appb-000218
Figure PCTCN2018073989-appb-000218
500mL三口瓶中依次加入3-溴-4-氟苯硫醇(14g,68.0mmol),乙腈(200mL)。室温下分五批加入碘苯二乙酸(21.9g,68.0mmol)。室温反应1小时后加水(100mL)淬灭,浓缩,乙酸乙酯(100mL×2)萃取,无水硫酸钠干燥,柱分离(石油醚)得到1,2-二(3-溴-4-氟苯基)二硫烷(14g,黄色油状物,产率100%)。3-Bromo-4-fluorobenzenethiol (14 g, 68.0 mmol), acetonitrile (200 mL) was added to a 500 mL three-necked flask. Iodophthalic acid (21.9 g, 68.0 mmol) was added in five portions at room temperature. After reacting at room temperature for 1 hour, it was quenched with water (100 mL), concentrated, ethyl acetate (100 mL×2), and dried over anhydrous sodium sulfate. Phenyl) disulfane (14 g, yellow oil, yield 100%).
1H NMR(400MHz,CDCl 3):δ7.72–7.63(m,1H),7.39–7.28(m,1H),7.13–7.04(m,1H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.72 - 7.63 (m, 1H), 7.39 - 7.28 (m, 1H), 7.13 - 7.04 (m, 1H).
第四步:(3-溴-4-氟苯基)(环丙基)硫烷的制备.The fourth step: the preparation of (3-bromo-4-fluorophenyl) (cyclopropyl) sulane.
Figure PCTCN2018073989-appb-000219
Figure PCTCN2018073989-appb-000219
250mL三口瓶中依次加入1,2-二(3-溴-4-氟苯基)二硫烷(8g,19.4mmol),四氢呋喃(40mL)。氮气保护下于零下70℃滴加环丙基溴化镁(60mL,1M,60mmol)。反应1小时后加饱和NH 4Cl(100mL)淬灭,乙酸乙酯(100mL×2)萃取,无水硫酸钠干燥,柱分离(石油醚)得到(3-溴-4-氟苯基)(环丙基)硫烷(4.3g,黄色油状物,产率90%)。 1,2-bis(3-bromo-4-fluorophenyl)disulfane (8 g, 19.4 mmol) and tetrahydrofuran (40 mL) were sequentially added to a 250 mL three-necked flask. Cyclopropylmagnesium bromide (60 mL, 1 M, 60 mmol) was added dropwise at 70 ° C under nitrogen. After 1 hour the reaction was added saturated NH 4 Cl (100mL) was quenched with ethyl acetate (100mL × 2) and extracted, dried over anhydrous sodium sulfate, and separated by column (petroleum ether) to give (3-bromo-4-fluorophenyl) ( Cyclopropyl)sulfane (4.3 g, yellow oil, yield 90%).
1H NMR(400MHz,DMSO-d 6):δ7.65(s,1H),7.40–7.31(m,2H),2.35(m,4.3Hz,1H),1.13–1.06(m,2H),0.63–0.56(m,2H). 1 H NMR (400MHz, DMSO- d 6): δ7.65 (s, 1H), 7.40-7.31 (m, 2H), 2.35 (m, 4.3Hz, 1H), 1.13-1.06 (m, 2H), 0.63 –0.56(m,2H).
第五步:2-溴-4-(环丙基磺酰)-1-氟苯的制备Step 5: Preparation of 2-bromo-4-(cyclopropylsulfonyl)-1-fluorobenzene
Figure PCTCN2018073989-appb-000220
Figure PCTCN2018073989-appb-000220
(3-溴-4-氟苯基)(环丙基)硫烷(4.0g,6.50mmol),溶于二氯甲烷(20mL),0℃滴加间氯过氧苯甲酸(2.90g,14.31mmol)的二氯甲烷溶液(20mL)。反应在零度下搅拌一个小时,反应完全。将反应液用饱和的硫代硫酸钠(20mL)洗,然后用碳酸氢钠水溶液(40mL×2),水(40mL×2)和饱和食盐水(40mL)洗涤,并用无水硫酸钠干燥,浓缩后柱层析得到化合物2-溴-4-(环丙基磺酰)-1-氟苯(4.0g,产 率89%)。(3-Bromo-4-fluorophenyl)(cyclopropyl)sulfane (4.0 g, 6.50 mmol), dissolved in dichloromethane (20 mL), m. m. Methylene chloride solution (20 mL). The reaction was stirred at zero for one hour and the reaction was complete. The reaction mixture was washed with EtOAc EtOAc (EtOAc) After column chromatography, the compound 2-bromo-4-(cyclopropylsulfonyl)-1-fluorobenzene (4.0 g, yield 89%) was obtained.
第六步:4-(5-(环丙基磺酰)-2-氟苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备Step 6: Preparation of 4-(5-(cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000221
Figure PCTCN2018073989-appb-000221
2-溴-4-(环丙基磺酰)-1-氟苯(1.9g,6.81mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(2.25g,5.46mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(399mg,0.54mmol),碳酸钾(1.88g,13.66mmol)溶于1,4-二氧六环(24mL)和水(6mL)的混合溶剂,在氮气保护下100℃反应搅拌4小时后反应完全。将反应液倒入水中(50mL),用乙酸乙酯萃取(50mL×2),合并有机相后用水洗(100mL),饱和食盐水洗(100mL),柱层析(石油醚:乙酸乙酯=3:1,V/V)得到化合物4-(5-(环丙基磺酰)-2-氟苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(1.38g,产率52%)。2-bromo-4-(cyclopropylsulfonyl)-1-fluorobenzene (1.9 g, 6.81 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3, 2-Dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (2.25 g, 5.46 mmol), [1,1'-bis(diphenyl) Phosphyl)ferrocene]palladium dichloride (399 mg, 0.54 mmol), potassium carbonate (1.88 g, 13.66 mmol) dissolved in a mixed solvent of 1,4-dioxane (24 mL) and water (6 mL) The reaction was completed after stirring at 100 ° C for 4 hours under a nitrogen atmosphere. The reaction mixture was poured into water (50 mL), EtOAc (EtOAc (EtOAc)EtOAc. :1, V/V) gave the compound 4-(5-(cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b Pyridine (1.38 g, yield 52%).
第七步:4-(5-(环丙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Step 7: Preparation of 4-(5-(cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine
4-(5-(环丙基磺酰)-2-氟苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(1.28g,2.64mmol)溶于叔丁醇(20mL)和四氢呋喃(5mL)的混合溶剂中,加入氢氧化钾(3M,10mL),在70℃搅拌反应过夜后降至室温。将反应液旋干后加入水(20mL),然后用乙酸乙酯萃取(2×20mL),合并有机相后依次用水(40mL)和饱和食盐水(40mL)洗涤,并用无水硫酸钠干燥,浓缩后柱层析(石油醚:乙酸乙酯=3:1,V/V)得到4-(5-(环丙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(670mg,产率77%)。4-(5-(Cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (1.28 g, 2.64 mmol) In a mixed solvent of tert-butanol (20 mL) and tetrahydrofuran (5 mL), potassium hydroxide (3M, 10 mL) was added, and the mixture was stirred at 70 ° C overnight and then cooled to room temperature. The reaction mixture was dried with EtOAc EtOAc (EtOAc) After column chromatography (petroleum ether: ethyl acetate = 3:1, V/V) gave 4-(5-(cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrole [2,3-b]pyridine (670 mg, yield 77%).
第八步:4-(5-(环丙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 8: Preparation of 4-(5-(cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000223
Figure PCTCN2018073989-appb-000223
4-(5-(环丙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(670.0mg,2.03mmol),溶于四氢呋喃(7mL)中,室温下加入间氯过氧苯甲酸(616mg,3.04mmol),室温下下搅拌十分钟,将反应液用硫代硫酸钠(20mL)淬灭,然后用乙酸乙酯(20mL×2)萃取,有机相合并后用碳酸氢钠的水溶液(20mL)洗,水洗(20mL)和饱和食盐水(20mL)洗涤,并用无水硫酸钠干燥,浓缩后柱层析(二氯甲烷:甲醇=20:1,V/V)得到化合物4-(5-(环丙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(410mg,产率58%)。4-(5-(Cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (670.0 mg, 2.03 mmol), dissolved in tetrahydrofuran (7 mL) To the mixture, m-chloroperoxybenzoic acid (616 mg, 3.04 mmol) was added at room temperature, and the mixture was stirred at room temperature for ten minutes. The reaction mixture was quenched with sodium thiosulfate (20 mL) and then ethyl acetate (20mL×2) The organic phase was combined and washed with aqueous sodium hydrogen carbonate (20 mL), washed with water (20 mL) and brine (20 mL) and dried over anhydrous sodium sulfate. :1, V/V) gave the compound 4-(5-(cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxidation (410 mg, yield 58%).
第九步:4-(5-(环丙基磺酰)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 9: 4-(5-(Cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Preparation of pyridine-7-oxide
Figure PCTCN2018073989-appb-000224
Figure PCTCN2018073989-appb-000224
4-(5-(环丙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(20.0mg,0.057mmol)溶于N-甲基吡咯烷酮(2mL),冰浴下加入2,4-二氟苯酚((23mg,0.17mmol),碳酸铯(87mg,0.267mmol),微波180℃下反应30分钟后冷却至室温,然后用氯化铵的水溶液(10mL)淬灭,,乙酸乙酯萃取(10mL×2)。合并有机相后用水(10mL×2)和饱和食盐水(10mL)洗涤,并用无水硫酸钠干燥,浓缩后通过制备色谱得到化合物4-(5-(环丙基磺酰)-2-(2,4-二氟苯氧基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(9.0mg,产率34%)。4-(5-(Cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (20.0 mg, 0.057 mmol) To N-methylpyrrolidone (2 mL), 2,4-difluorophenol ((23 mg, 0.17 mmol), cesium carbonate (87 mg, 0.267 mmol) was added under ice-cooling, and the mixture was reacted at 180 ° C for 30 minutes, and then cooled to room temperature. The organic layer was washed with water (10 mL×2) and brine (10 mL) and dried over anhydrous sodium sulfate. After concentration, by preparative chromatography to give the compound 4-(5-(cyclopropylsulfonyl)-2-(2,4-difluorophenoxy)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide (9.0 mg, yield 34%).
1H NMR(400MHz,CD 3OD):δ7.99(d,J=2.3Hz,1H),7.85(dd,J=8.7Hz,2.3Hz,1H),7.35(d,J=3.4Hz,1H),7.27(s,1H),7.15(td,J=9.1,5.5Hz,1H),7.06(ddd,J=11.2Hz,8.6Hz,3.0Hz,1H),6.96(dd,J=8.7Hz,0.8Hz,1H),6.90(tdd,J=9.Hz 4,2.9Hz,1.7Hz,1H),6.48(d,J=3.4Hz,1H),2.69–2.62(m,1H),2.61(s,3H),1.16(qd,J=5.5Hz,1.2Hz,2H),0.99(qd,J=5.5Hz,1.2Hz,2H). 1 H NMR (400 MHz, CD 3 OD): δ 7.99 (d, J = 2.3 Hz, 1H), 7.85 (dd, J = 8.7 Hz, 2.3 Hz, 1H), 7.35 (d, J = 3.4 Hz, 1H) ), 7.27 (s, 1H), 7.15 (td, J = 9.1, 5.5 Hz, 1H), 7.06 (ddd, J = 11.2 Hz, 8.6 Hz, 3.0 Hz, 1H), 6.96 (dd, J = 8.7 Hz, 0.8Hz, 1H), 6.90 (tdd, J=9.Hz 4, 2.9Hz, 1.7Hz, 1H), 6.48(d, J=3.4Hz, 1H), 2.69–2.62(m,1H), 2.61(s , 3H), 1.16 (qd, J = 5.5 Hz, 1.2 Hz, 2H), 0.99 (qd, J = 5.5 Hz, 1.2 Hz, 2H).
MS m/z(ESI):457.1[M+H] +MS m/z (ESI): 457.1 [M+H] + .
实施例82Example 82
4-(2-(4-溴-2-氟苯氧基)-5-(环丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-Bromo-2-fluorophenoxy)-5-(cyclopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 -oxide
Figure PCTCN2018073989-appb-000225
Figure PCTCN2018073989-appb-000225
按照实施例81第9步的实验步骤,用4-溴-2-氟苯酚代替2,4-二氟苯酚为原料,得到化合物4-(2-(4-溴-2-氟苯氧基)-5-(环丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(8.4mg,产率29%)。According to the experimental procedure of the first step of Example 81, 4-bromo-2-fluorophenol was used instead of 2,4-difluorophenol to obtain the compound 4-(2-(4-bromo-2-fluorophenoxy). 5-(-Cyclopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (8.4 mg, yield 29%).
1H NMR(400MHz,CDCl3):δ12.54(s,1H),8.09(d,J=2.2Hz,1H),7.86(dd,J=8.7Hz,2.3Hz,1H),7.38(dd,J=9.8Hz,2.2Hz,1H),7.32(d,J=3.3Hz,1H),7.29(s,1H),7.21(s,1H),6.95(t,J=8.4Hz,2H),6.51(d,J=3.3Hz,1H),2.77(s,3H),2.60–2.44(m,1H),1.43–1.34(m,2H),1.13–1.00(m,2H). 1 H NMR (400MHz, CDCl3) : δ12.54 (s, 1H), 8.09 (d, J = 2.2Hz, 1H), 7.86 (dd, J = 8.7Hz, 2.3Hz, 1H), 7.38 (dd, J = 9.8 Hz, 2.2 Hz, 1H), 7.32 (d, J = 3.3 Hz, 1H), 7.29 (s, 1H), 7.21 (s, 1H), 6.95 (t, J = 8.4 Hz, 2H), 6.51 ( d, J = 3.3 Hz, 1H), 2.77 (s, 3H), 2.60 - 2.44 (m, 1H), 1.43 - 1.34 (m, 2H), 1.13 - 1.00 (m, 2H).
MS m/z(ESI):517.1[M+H] +MS m/z (ESI): 517.1 [M+H] + .
实施例83Example 83
4-(5-(环丙基磺酰)-2-(((1r,4r)-4-羟基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(cyclopropylsulfonyl)-2-(((1r,4r)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000226
Figure PCTCN2018073989-appb-000226
第一步:4-(5-(环丙基磺酰)-2-(((1r,4r)-4-羟基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备First step: 4-(5-(cyclopropylsulfonyl)-2-(((1r,4r)-4-hydroxycyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[ Preparation of 2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000227
Figure PCTCN2018073989-appb-000227
4-(5-(环丙基磺酰)-2-氟苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(20.0mg,0.057mmol)溶于N,N-二甲基甲酰胺(2mL),冰浴下加入(1r,4r)-环己烷-1,4-二醇((40mg,0.34mmol),氢化钠(7mg,0.17mmol),室温搅拌过夜后用氯化铵的水溶液(10mL)淬灭,乙酸乙酯萃取(10mL×2)。合并有机相后用水(10mL×2)和饱和食盐水(10mL)洗涤,并用无水硫酸钠干燥,浓缩后通过制备色谱得到化合物4-(5-(环丙基磺酰)-2-(((1r,4r)-4-羟基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(2.0mg,产率8%)。4-(5-(Cyclopropylsulfonyl)-2-fluorophenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (20.0 mg, 0.057 mmol) Add (1r,4r)-cyclohexane-1,4-diol (40mg, 0.34mmol), sodium hydride (7mg, 0.17mmol) in N,N-dimethylformamide (2mL). After stirring overnight at room temperature, it was quenched with EtOAc EtOAc EtOAc (EtOAc) The sodium is dried and concentrated to give the compound 4-(5-(cyclopropylsulfonyl)-2-(((1r,4r)-4-hydroxycyclohexyl)oxy)phenyl)-6-methyl. -1H-pyrrolo[2,3-b]pyridine-7-oxide (2.0 mg, yield 8%).
1H NMR(400MHz,CD 3OD):δ8.33(s,1H),7.98–7.70(m,2H),7.39–7.21(m,2H),7.18(s,1H),6.35(d,J=3.4Hz,1H),4.50(d,J=3.3Hz,2H),3.60–3.44 (m,1H),2.64(dd,J=7.9Hz,4.7Hz,1H),2.61(s,3H),1.96(s,2H),1.68(s,2H),1.45–1.25(m,4H),1.19–1.06(m,2H),1.04–0.87(m,2H). 1 H NMR (400 MHz, CD 3 OD): δ 8.33 (s, 1H), 7.98 - 7.70 (m, 2H), 7.39 - 7.21 (m, 2H), 7.18 (s, 1H), 6.35 (d, J) = 3.4 Hz, 1H), 4.50 (d, J = 3.3 Hz, 2H), 3.60 - 3.44 (m, 1H), 2.64 (dd, J = 7.9 Hz, 4.7 Hz, 1H), 2.61 (s, 3H), 1.96 (s, 2H), 1.68 (s, 2H), 1.45 - 1.25 (m, 4H), 1.19 - 1.06 (m, 2H), 1.04 - 0.87 (m, 2H).
MS m/z(ESI):443.1[M+H] +MS m/z (ESI): 443.1 [M+H] + .
实施例84Example 84
4-(5-(环丙基磺酰)-2-(((反式)-4-乙基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(cyclopropylsulfonyl)-2-(((trans)-4-ethylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000228
Figure PCTCN2018073989-appb-000228
按照实施例83的实验步骤,用反-4-乙基环己醇代替(1r,4r)-环己烷-1,4-二醇为原料,得到4-(5-(环丙基磺酰)-2-(((反式)-4-乙基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.02g,白色固体,产率:38%)。Following the experimental procedure of Example 83, substituting trans-4-ethylcyclohexanol for (1r,4r)-cyclohexane-1,4-diol as starting material gave 4-(5-(cyclopropylsulfonyl) )-2-(((trans)-4-ethylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.02 g , white solid, yield: 38%).
MS m/z(ESI):455.2[M+H] +. MS m/z (ESI): 455.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ12.27(br,1H),7.95(d,J=2.4Hz,1H),7.89(dd,J=8.4Hz,2.4Hz,1H),7.34(d,J=3.2Hz,1H),7.15-7.11(m,2H),6.42(d,J=3.2Hz,1H),4.36-4.26(m,1H),2.77(s,3H),2.52-2.46(m,1H),2.16-2.08(m,2H),1.84-1.81(m,2H),1.37-1.20(m,6H),1.16-1.07(m,1H),1.07-0.95(m,4H),0.87(d,J=7.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.27 (br, 1H), 7.95 (d, J = 2.4Hz, 1H), 7.89 (dd, J = 8.4Hz, 2.4Hz, 1H), 7.34 (d, J=3.2 Hz, 1H), 7.15-7.11 (m, 2H), 6.42 (d, J=3.2 Hz, 1H), 4.36-4.26 (m, 1H), 2.77 (s, 3H), 2.52-2.46 (m) , 1H), 2.16-2.08 (m, 2H), 1.84-1.81 (m, 2H), 1.37-1.20 (m, 6H), 1.16-1.07 (m, 1H), 1.07-0.95 (m, 4H), 0.87 (d, J = 7.6 Hz, 3H).
实施例85Example 85
4-(5-(环丙基磺酰)-2-(((反式)-4-异丙基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(cyclopropylsulfonyl)-2-(((trans)-4-isopropylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000229
Figure PCTCN2018073989-appb-000229
按照实施例83的实验步骤,用反-4-异丙基环己醇代替(1r,4r)-环己烷-1,4-二醇为原料,得到4-(5-(环丙基磺酰)-2-(((反式)-4-异丙基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.020g,白色固体,产率:43%)。Following the experimental procedure of Example 83, using trans-4-isopropylcyclohexanol instead of (1r,4r)-cyclohexane-1,4-diol as the starting material gave 4-(5-(cyclopropylsulfonyl) Acyl)-2-(((trans)-4-isopropylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide ( 0.020 g, white solid, yield: 43%).
MS m/z(ESI):469.2[M+H] +. MS m/z (ESI): 469.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ12.55(br,1H),7.96(d,J=2.4Hz,1H),7.89(dd,J=8.8Hz,2.4Hz,1H),7.31(d,J=3.2Hz,1H),7.15-7.13(m,2H),6.40(d,J=3.2Hz,1H),4.32-4.25(m,1H),2.77(s,3H),2.52-2.46(m,1H),2.14-2.11(m,2H), 1.80-1.77(m,2H),1.48-1.40(m,1H),1.37-1.26(m,4H),1.16-1.02(m,5H),0.86(t,J=6.8Hz,6H). 1 H NMR (400MHz, CDCl 3 ): δ12.55 (br, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.89 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.31 (d, J=3.2 Hz, 1H), 7.15-7.13 (m, 2H), 6.40 (d, J=3.2 Hz, 1H), 4.32-4.25 (m, 1H), 2.77 (s, 3H), 2.52-2.46 (m) ,1H),2.14-2.11(m,2H), 1.80-1.77(m,2H), 1.48-1.40(m,1H),1.37-1.26(m,4H),1.16-1.02(m,5H),0.86 (t, J = 6.8 Hz, 6H).
实施例86Example 86
4-(5-(环丙基磺酰)-2-(((反式)-4-丙基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(cyclopropylsulfonyl)-2-(((trans)-4-propylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000230
Figure PCTCN2018073989-appb-000230
按照实施例83的实验步骤,用反-4-异丙基环己醇代替(1r,4r)-环己烷-1,4-二醇为原料,得到4-(5-(环丙基磺酰)-2-(((反式)-4-异丙基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.080g,白色固体,产率:50%)。Following the experimental procedure of Example 83, using trans-4-isopropylcyclohexanol instead of (1r,4r)-cyclohexane-1,4-diol as the starting material gave 4-(5-(cyclopropylsulfonyl) Acyl)-2-(((trans)-4-isopropylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide ( 0.080 g, white solid, yield: 50%).
MS m/z(ESI):469.2[M+H] +. MS m/z (ESI): 469.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.62(s,1H),7.96(d,J=2.0Hz,1H),7.90(dd,J=8.8Hz,2.0Hz,1H),7.33(d,J=3.2Hz,1H),7.15-7.13(m,2H),6.45(d,J=3.2Hz,1H),4.34-4.27(m,1H),2.76(s,3H),2.52-2.46(m,1H),2.10-2.05(m,2H),1.82-1.75(m,2H),1.38-1.14(m,9H),1.07-0.94(m,4H),0.87(t,J=7.6Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.62 (s, 1H), 7.96 (d, J = 2.0Hz, 1H), 7.90 (dd, J = 8.8Hz, 2.0Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.15-7.13 (m, 2H), 6.45 (d, J=3.2 Hz, 1H), 4.34-4.27 (m, 1H), 2.76 (s, 3H), 2.52-2.46 (m) , 1H), 2.10-2.05 (m, 2H), 1.82-1.75 (m, 2H), 1.38-1.14 (m, 9H), 1.07-0.94 (m, 4H), 0.87 (t, J = 7.6 Hz, 3H ).
实施例87Example 87
4-(5-(环丙基磺酰)-2-(((反式)-4-叔丁基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(cyclopropylsulfonyl)-2-(((trans)-4-tert-butylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide
Figure PCTCN2018073989-appb-000231
Figure PCTCN2018073989-appb-000231
按照实施例83的实验步骤,用反-4-叔丁基环己醇代替(1r,4r)-环己烷-1,4-二醇为原料,得到4-(5-(环丙基磺酰)-2-(((反式)-4-叔丁基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.025g,白色固体,产率:36%)。Following the experimental procedure of Example 83, substituting trans-t-t-butylcyclohexanol for (1r,4r)-cyclohexane-1,4-diol as starting material gave 4-(5-(cyclopropylsulfonyl) -2-(((trans)-4-tert-butylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.025 g, white Solid, yield: 36%).
MS m/z(ESI):483.2[M+H] +. MS m/z (ESI): 483.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.76(s,1H),7.96(d,J=2.4Hz,1H),7.90(dd,J=8.4Hz,2.8Hz,1H),7.36(d,J=3.2Hz,1H),7.17-7.14(m,2H),6.44(d,J=3.2Hz,1H),4.32-4.24(m,1H),2.76(s,3H),2.52-2.46(m,1H),2.16-2.13(m,2H),1.86-1.83(m,2H),1.38-1.25(m,4H),1.04-1.01(m,5H),0.86(s,9H). 1 H NMR (400MHz, CDCl 3 ): δ11.76 (s, 1H), 7.96 (d, J = 2.4Hz, 1H), 7.90 (dd, J = 8.4Hz, 2.8Hz, 1H), 7.36 (d, J=3.2 Hz, 1H), 7.17-7.14 (m, 2H), 6.44 (d, J=3.2 Hz, 1H), 4.32-4.24 (m, 1H), 2.76 (s, 3H), 2.52-2.46 (m) , 1H), 2.16-2.13 (m, 2H), 1.86-1.83 (m, 2H), 1.38-1.25 (m, 4H), 1.04-1.01 (m, 5H), 0.86 (s, 9H).
实施例88Example 88
4-(2-(((1S,2R,5S)-2-异丙基-5-甲基环己基)氧代)-5-(环丙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-((1S,2R,5S)-2-isopropyl-5-methylcyclohexyl)oxo)-5-(cyclopropanesulfonyl)phenyl)-6-methyl-1H -pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000232
Figure PCTCN2018073989-appb-000232
按照实施例83的实验步骤,用L-薄荷醇代替(1r,4r)-环己烷-1,4-二醇为原料,得到4-(2-(((1S,2R,5S)-2-异丙基-5-甲基环己基)氧代)-5-(环丙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化(0.020g,白色固体,产率36%)。Following the experimental procedure of Example 83, L-menthol was used instead of (1r,4r)-cyclohexane-1,4-diol to give 4-(2-((1S,2R,5S)-2). -isopropyl-5-methylcyclohexyl)oxo)-5-(cyclopropanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxidation ( 0.020 g, white solid, yield 36%).
MS m/z(ESI):483.2[M+H] +. MS m/z (ESI): 483.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.68(br,1H),7.95-7.92(m,2H),7.43(d,J=3.2Hz,1H),7.20-7.17(m,2H),6.48(d,J=2.4Hz,1H),4.28-4.21(m,1H),2.78(s,3H),2.53-2.46(m,1H),2.19-2.15(m,1H),1.93-1.82(m,1H),1.75-1.64(m,2H),1.56-1.44(m,1H),1.39-1.30(m,3H),1.09-0.99(m,3H),0.94-0.90(m,5H),0.78(d,J=7.2Hz,3H),0.67(d,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ11.68 (br, 1H), 7.95-7.92 (m, 2H), 7.43 (d, J = 3.2Hz, 1H), 7.20-7.17 (m, 2H), 6.48 (d, J=2.4 Hz, 1H), 4.28-4.21 (m, 1H), 2.78 (s, 3H), 2.53-2.46 (m, 1H), 2.19-2.15 (m, 1H), 1.93-1.82 (m) , 1H), 1.75-1.64 (m, 2H), 1.56-1.44 (m, 1H), 1.39-1.30 (m, 3H), 1.09-0.99 (m, 3H), 0.94-0.90 (m, 5H), 0.78 (d, J = 7.2 Hz, 3H), 0.67 (d, J = 7.2 Hz, 3H).
实施例89Example 89
4-(2-(环丙基甲氧基)-5-(环丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(cyclopropylmethoxy)-5-(cyclopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000233
Figure PCTCN2018073989-appb-000233
按照实施例83的实验步骤,用环丙甲醇代替(1r,4r)-环己烷-1,4-二醇为原料,得到4-(2-(环丙基甲氧基)-5-(环丙基磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(27.5mg,产率47.6%)。Following the experimental procedure of Example 83, cyclopropanol was used instead of (1r,4r)-cyclohexane-1,4-diol to give 4-(2-(cyclopropylmethoxy)-5-( Cyclopropylsulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (27.5 mg, yield 47.6%).
1H NMR(400MHz,CDCl 3):δ12.49(s,1H),7.99(d,J=2.4Hz,1H),7.93-7.90(dd,J=8.8Hz,2.4Hz,1H),7.35-7.34(d,J=3.2Hz,1H),7.21(s,1H),7.13-7.11(d,J=8.8Hz,1H),6.44(d,J=3.2Hz,1H),3.96–3.92(d,J=6.8Hz,2H),2.78(s,3H),2.50–2.47(m,1H),1.37–1.34(m,2H),1.17-1.15(m,1H),1.07–1.04(m,2H),0.62–0.60(m,2H),0.32–0.30(m,2H). 1 H NMR (400 MHz, CDCl 3 ): δ 12.49 (s, 1H), 7.99 (d, J = 2.4 Hz, 1H), 7.93 - 7.90 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.35- 7.34 (d, J = 3.2 Hz, 1H), 7.21 (s, 1H), 7.13 - 7.11 (d, J = 8.8 Hz, 1H), 6.44 (d, J = 3.2 Hz, 1H), 3.96 - 3.92 (d , J=6.8Hz, 2H), 2.78(s,3H), 2.50–2.47(m,1H), 1.37–1.34(m,2H),1.17-1.15(m,1H),1.07–1.04(m,2H ), 0.62–0.60 (m, 2H), 0.32–0.30 (m, 2H).
MS m/z(ESI):399.1[M+H] +MS m/z (ESI): 399.1 [M+H] + .
实施例90Example 90
4-(5-(环丙基磺酰)-2-((4,4-二氟环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(cyclopropylsulfonyl)-2-((4,4-difluorocyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide
Figure PCTCN2018073989-appb-000234
Figure PCTCN2018073989-appb-000234
按照实施例83的实验步骤,用4,4-二氟环己烷代替(1r,4r)-环己烷-1,4-二醇为原料,得4-(5-(环丙基磺酰)-2-((4,4-二氟环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(32.0mg,产率47.8%).Following the experimental procedure of Example 83, 4,4-difluorocyclohexane was used instead of (1r,4r)-cyclohexane-1,4-diol to give 4-(5-(cyclopropylsulfonyl). --2-((4,4-Difluorocyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (32.0 mg, yield 47.8%).
1H NMR(400MHz,CDCl 3):δ12.49(s,1H),8.00(d,J=2.4Hz,1H),7.94(dd,J=8.8Hz,2.4Hz,1H),7.36(d,J=3.2Hz,1H),7.17-7.15(d,J=8.8Hz,1H),7.12(s,1H),6.42(d,J=3.2Hz,1H),4.66–4.64(m,1H),2.77(s,3H),2.49–2.47(m,1H),1.96–1.73(m,8H),1.38-1.36(m,2H),1.17–1.14(m,2H)。 1 H NMR (400MHz, CDCl 3 ): δ12.49 (s, 1H), 8.00 (d, J = 2.4Hz, 1H), 7.94 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.36 (d, J = 3.2 Hz, 1H), 7.17-7.15 (d, J = 8.8 Hz, 1H), 7.12 (s, 1H), 6.42 (d, J = 3.2 Hz, 1H), 4.66 - 4.64 (m, 1H), 2.77 (s, 3H), 2.49 - 2.47 (m, 1H), 1.96 - 1.73 (m, 8H), 1.38-1.36 (m, 2H), 1.17 - 1.14 (m, 2H).
MS m/z(ESI):463.1[M+H] + MS m/z (ESI): 463.1 [M+H] +
实施例91Example 91
4-(5-(环丙基磺酰)-2-(((1r,4r)-4-甲基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(cyclopropylsulfonyl)-2-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000235
Figure PCTCN2018073989-appb-000235
按照实施例83的实验步骤,用(1r,4r)-4-甲基环己烷-1-醇代替(1r,4r)-环己烷-1,4-二醇为原料,得到化合物4-(5-(环丙基磺酰)-2-(((1r,4r)-4-甲基环己基)氧代)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(24.4mg,产率32%)。Following the experimental procedure of Example 83, (1r,4r)-4-methylcyclohexane-1-ol was used instead of (1r,4r)-cyclohexane-1,4-diol to give compound 4- (5-(Cyclopropylsulfonyl)-2-(((1r,4r)-4-methylcyclohexyl)oxo)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide (24.4 mg, yield 32%).
1H NMR(400MHz,CD 3OD):δ7.89–7.81(m,2H),7.34–7.27(m,2H),7.16(s,1H),6.34(d,J=3.2Hz,1H),4.41–4.31(m,1H),2.67–2.57(m,4H),2.04–1.95(m,2H),1.69–1.60(m,2H),1.33–1.10(m,5H),1.06–0.94(m,4H),0.81(d,J=6.4Hz,3H)。 1 H NMR (400 MHz, CD 3 OD): δ 7.89 - 7.81 (m, 2H), 7.34 - 7.27 (m, 2H), 7.16 (s, 1H), 6.34 (d, J = 3.2 Hz, 1H), 4.41–4.31 (m, 1H), 2.67–2.57 (m, 4H), 2.04–1.95 (m, 2H), 1.69–1.60 (m, 2H), 1.33–1.10 (m, 5H), 1.06–0.94 (m) , 4H), 0.81 (d, J = 6.4 Hz, 3H).
MS m/z(ESI):441.1[M+H] + MS m/z (ESI): 441.1 [M+H] +
实施例92Example 92
4-(5-(环丙基磺酰)-2-(((1r,4r)-4-甲基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(cyclopropylsulfonyl)-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000236
Figure PCTCN2018073989-appb-000236
按照实施例83的实验步骤,用(1r,4r)-4-甲基环己胺代替(1r,4r)-环己烷-1,4-二醇为原料得到化合物4-(5-(环丙基磺酰)-2-(((1r,4r)-4-甲基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(23.4mg,产率:38%)。Following the experimental procedure of Example 83, substituting (1r,4r)-4-methylcyclohexylamine for (1r,4r)-cyclohexane-1,4-diol as the starting material gave the compound 4-(5-(ring) Propylsulfonyl)-2-(((1r,4r)-4-methylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxidation (23.4 mg, yield: 38%).
1H NMR(400MHz,CDCl 3):δ12.18(s,1H),7.76(dd,J=8.7Hz,2.2Hz,1H),7.66(d,J=2.4Hz,1H),7.34(d,J=3.2Hz,1H),7.06(s,1H),6.78(d,J=8.8Hz,1H),6.36(d,J=3.2Hz,1H),4.27(d,J=7.6Hz,1H),3.38–3.23(m,1H),2.77(s,3H),2.52–2.42(m,1H),2.10–1.97(m,2H),1.73–1.67(m,2H),1.36–1.27(m,3H),1.11–0.94(m,6H),0.90(d,J=6.4Hz,3H)。 1 H NMR (400MHz, CDCl 3 ): δ12.18 (s, 1H), 7.76 (dd, J = 8.7Hz, 2.2Hz, 1H), 7.66 (d, J = 2.4Hz, 1H), 7.34 (d, J = 3.2 Hz, 1H), 7.06 (s, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 3.2 Hz, 1H), 4.27 (d, J = 7.6 Hz, 1H) , 3.38–3.23 (m, 1H), 2.77 (s, 3H), 2.52–2.42 (m, 1H), 2.10–1.97 (m, 2H), 1.73–1.67 (m, 2H), 1.36–1.27 (m, 3H), 1.11 - 0.94 (m, 6H), 0.90 (d, J = 6.4 Hz, 3H).
MS m/z(ESI):440.2[M+H] + MS m/z (ESI): 440.2 [M+H] +
实施例93Example 93
4-(5-(环丙基磺酰)-2-(((反式)-4-乙基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(cyclopropylsulfonyl)-2-(((trans)-4-ethylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide
Figure PCTCN2018073989-appb-000237
Figure PCTCN2018073989-appb-000237
第一步:N-(4-乙基环己基)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(环丙磺酰)苯胺First step: N-(4-ethylcyclohexyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(cyclopropanesulfonyl)aniline
Figure PCTCN2018073989-appb-000238
Figure PCTCN2018073989-appb-000238
在10毫升微波管中加入4-(2-氟-5-(环丙磺酰)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶7-氧(0.060g,0.17mmol),4-乙基环己胺(0.3mL)和N-甲基吡咯烷酮(3mL),在油浴中加热至140℃,反应过夜,冷却至室温。反应液用乙酸乙酯(20mL)稀释,盐水(20mL)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,得粗产物N-(4-乙基环己基)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(环丙磺酰)苯胺(0.08g,黄色油状物),直接用于下一步反应。Add 4-(2-fluoro-5-(cyclopropanesulfonyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine 7-oxo (0.060 g, in a 10 ml microwave tube). 0.17 mmol), 4-ethylcyclohexylamine (0.3 mL) and N-methylpyrrolidone (3 mL) were heated to 140 ° C in an oil bath and allowed to react overnight and then cooled to room temperature. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(cyclopropanesulfonyl)aniline (0.08 g, yellow oil) was used directly for next step.
MS m/z(ESI):438.2[M+H] +. MS m/z (ESI): 438.2 [M+H] + .
第二步:4-(5-(环丙基磺酰)-2-(((反式)-4-乙基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物Second step: 4-(5-(cyclopropylsulfonyl)-2-(((trans)-4-ethylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2 ,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000239
Figure PCTCN2018073989-appb-000239
将粗产物N-(4-乙基环己基)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(环丙磺酰)苯胺(0.080g,黄色油状物)溶解于二氯甲烷中(20mL),然后将间氯过氧苯甲酸(85%,0.045g,0.22mmol)加入到反应液中,室温搅拌两小时。反应结束后,反应液用二氯甲烷(20mL)稀释,饱和碳酸氢钠溶液(20mL)洗涤,盐水(20mL)洗涤,无水硫酸钠干燥,过滤,旋干,粗产物用反相制备色谱分离得到4-(5-(环丙基磺酰)-2-(((反式)-4-乙基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.013g,白色固体,产率16%)。The crude product N-(4-ethylcyclohexyl)-2-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(cyclopropanesulfonyl)aniline ( 0.080 g (yellow oil) was dissolved in dichloromethane (20 mL), then m-chloroperoxybenzoic acid (85%, 0.045 g, 0.22 mmol) was added to the reaction mixture and stirred at room temperature for two hours. After completion of the reaction, the reaction mixture was diluted with methylene chloride (20 mL), EtOAc (EtOAc) 4-(5-(Cyclopropylsulfonyl)-2-(((trans)-4-ethylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3- b] Pyridine-7-oxide (0.013 g, white solid, yield 16%).
MS m/z(ESI):454.2[M+H] +. MS m/z (ESI): 454.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ12.29(br,1H),7.77(dd,J=8.8Hz,2.4Hz,1H),7.67(d,J=2.4Hz 1H),7.44(d,J=2.8Hz,1H),7.11(s,1H),6.80(d,J=8.8Hz,1H),6.42(d,J=2.8Hz,1H),4.28(d,J=7.6Hz,1H),3.32(br,1H),2.80(s,3H),2.50-2.43(m,1H),2.04(br,2H),1.80(br,2H),1.33-1.15(m,4H),1.14-0.93(m,7H),0.87(t,J=7.6Hz,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 12.29 (br, 1H), 7.77 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.67 (d, J = 2.4 Hz 1H), 7.44 (d, J) = 2.8 Hz, 1H), 7.11 (s, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.42 (d, J = 2.8 Hz, 1H), 4.28 (d, J = 7.6 Hz, 1H), 3.32(br,1H), 2.80(s,3H), 2.50-2.43(m,1H), 2.04(br,2H), 1.80(br,2H),1.33-1.15(m,4H),1.14-0.93( m, 7H), 0.87 (t, J = 7.6 Hz, 3H).
实施例94Example 94
4-(5-(环丙基磺酰)-2-(((顺式)-4-乙基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(5-(cyclopropylsulfonyl)-2-(((cis)-4-ethylcyclohexyl)amino)phenyl)-6-methyl-1H-pyrrolo[2,3-b Pyridine-7-oxide
Figure PCTCN2018073989-appb-000240
Figure PCTCN2018073989-appb-000240
按照实施例93的实验步骤,反相制备色谱分离同时得到4-(5-(环丙基磺酰)-2-(((顺式)-4-乙基环己基)氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.019g,白色固体,产率24%)。According to the experimental procedure of Example 93, reverse phase preparative chromatography gave 4-(5-(cyclopropylsulfonyl)-2-(((cis)-4-ethylcyclohexyl)amino)phenyl)- 6-Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (0.019 g, white solid, yield 24%).
MS m/z(ESI):454.2[M+H] +. MS m/z (ESI): 454.2 [M+H] + .
1H NMR(400MHz,CDCl 3):δ12.20(br,1H),7.78(dd,J=8.4Hz,2.0Hz,1H), 7.69(s,1H),7.45(s,1H),7.14(s,1H),6.79(d,J=8.4Hz,1H),6.48(d,J=2.0Hz,1H),4.52(d,J=6.4Hz,1H),3.66(br,1H),2.80(s,3H),2.50-2.44(m,1H),1.74-1.47(m,6H),1.33-1.29(m,2H),1.22-1.17(m,1H),1.16-1.13(m,2H),1.03-0.98(m,4H),0.83(t,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.20 (br, 1H), 7.78 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.69 (s, 1H), 7.45 (s, 1H), 7.14 ( s, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 4.52 (d, J = 6.4 Hz, 1H), 3.66 (br, 1H), 2.80 ( s, 3H), 2.50-2.44 (m, 1H), 1.74-1.47 (m, 6H), 1.33-1.29 (m, 2H), 1.22-1.17 (m, 1H), 1.16-1.13 (m, 2H), 1.03-0.98 (m, 4H), 0.83 (t, J = 7.2 Hz, 3H).
实施例95Example 95
4-(4-环丙基-2-(2,4-二氟苯氧基)-5-(乙基磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(4-cyclopropyl-2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[2,3- b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000241
Figure PCTCN2018073989-appb-000241
第一步:1-溴-2-(2,4-二氟苯氧基)-4-碘-5-硝基苯First step: 1-bromo-2-(2,4-difluorophenoxy)-4-iodo-5-nitrobenzene
Figure PCTCN2018073989-appb-000242
Figure PCTCN2018073989-appb-000242
室温下,将1-溴-2-氟-4-碘-5-硝基苯(1.07g,3.09mmol)溶解于乙腈(20mL)中,然后将2,4-二氟苯酚(0.80g,6.18mmol)和碳酸钠(0.66g,6.18mmol)加入到反应液中,室温搅拌过夜。反应结束后,反应液用乙酸乙酯稀释(40mL),有机相用盐水(20mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用柱层析分离(纯石油醚作为流动相)得到1-溴-2-(2,4-二氟苯氧基)-4-碘-5-硝基苯(0.53g,黄色固体,产率38%)。1-Bromo-2-fluoro-4-iodo-5-nitrobenzene (1.07 g, 3.09 mmol) was dissolved in acetonitrile (20 mL) at room temperature then 2,4-difluorophenol (0.80 g, 6.18) Methyl) and sodium carbonate (0.66 g, 6.18 mmol) were added to the reaction mixture and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was diluted with EtOAc EtOAc (EtOAc)EtOAc. Ether as the mobile phase gave 1-bromo-2-(2,4-difluorophenoxy)-4-iodo-5-nitrobenzene (0.53 g, mp.
第二步:1-溴-4-环丙基-2-(2,4-二氟苯氧基)-5-硝基苯The second step: 1-bromo-4-cyclopropyl-2-(2,4-difluorophenoxy)-5-nitrobenzene
Figure PCTCN2018073989-appb-000243
Figure PCTCN2018073989-appb-000243
室温下,将1-溴-2-(2,4-二氟苯氧基)-4-碘-5-硝基苯(0.53g,1.16mmol),环丙基硼酸(0.15g,1.74mmol),磷酸钾(0.49g,2.32mol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.085g,0.13mmol)溶解于无水二氧六环(10mL)中,氮气置换三次,加热至90℃,反应14小时。反应结束后,反应液用乙酸乙酯稀释(30mL),硅藻土过滤,滤液用盐水(30mL)洗涤,无水硫酸钠干燥,过滤,旋干,粗产物用柱层析分离(纯石油醚作为流动相)得到1-溴-4-环丙基-2-(2,4-二氟苯氧基)-5-硝基苯(0.35g,黄色固体,产率81%)。1-Bromo-2-(2,4-difluorophenoxy)-4-iodo-5-nitrobenzene (0.53 g, 1.16 mmol), cyclopropylboronic acid (0.15 g, 1.74 mmol) Potassium phosphate (0.49 g, 2.32 mol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.085 g, 0.13 mmol) were dissolved in anhydrous dioxane (10 mL) In the process, nitrogen was replaced three times, heated to 90 ° C, and reacted for 14 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc EtOAc EtOAc EtOAc. As mobile phase, 1-bromo-4-cyclopropyl-2-(2,4-difluorophenoxy)-5-nitrobenzene (0.35 g, yellow solid, yield 81%) was obtained.
第三步:5-溴-2-环丙基-4-(2,4-二氟苯氧基)苯胺The third step: 5-bromo-2-cyclopropyl-4-(2,4-difluorophenoxy)aniline
Figure PCTCN2018073989-appb-000244
Figure PCTCN2018073989-appb-000244
室温下,将1-溴-4-环丙基-2-(2,4-二氟苯氧基)-5-硝基苯(0.15g,0.41mol)和二水合二氯化锡(0.26g,1.13mol)溶解于乙醇(10mL)和水(0.5mL)中,室温搅拌14小时。反应结束后,在减压下将乙醇旋干,往残留物中加入冰水(15mL)和氢氧化钠水溶液(2M,15mL),水相用乙酸乙酯萃取(15mL×3),合并有机相,有机相用盐水(15mL×3)洗涤,无水硫酸钠干燥,过滤,旋干,粗产物用制备板分离得到5-溴-2-环丙基-4-(2,4-二氟苯氧基)苯胺(0.08g,产率:58%)。1-Bromo-4-cyclopropyl-2-(2,4-difluorophenoxy)-5-nitrobenzene (0.15 g, 0.41 mol) and tin dichloride dihydrate (0.26 g) at room temperature 1.13 mol) was dissolved in ethanol (10 mL) and water (0.5 mL) and stirred at room temperature for 14 hr. After the reaction was completed, the ethanol was evaporated to dryness. EtOAc (EtOAc) (EtOAc) The organic phase was washed with brine (15 mL×3), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The crude product was obtained from 5-bromo-2-cyclopropyl-4-(2,4-difluorobenzene. Oxy)aniline (0.08 g, yield: 58%).
MS m/z(ESI):340.0,342.0[M+H] +. MS m/z (ESI): 340.0, 342.0 [M+H] + .
第四步:N-(5-溴-2-环丙基-4-(2,4-二氟苯氧基)苯基)乙磺酰胺Fourth step: N-(5-bromo-2-cyclopropyl-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide
室温下,将5-溴-2-环丙基-4-(2,4-二氟苯氧基)苯胺(0.08g,0.24mmol)和吡啶(0.037g,0.47mmol)溶解于二氯甲烷(10mL)中,然后将乙基磺酰氯(0.06g,0.47mmol)滴加到反应体系中,加热至50℃,反应4小时。反应结束后,将二氯甲烷旋干,粗产物用乙酸乙酯(30mL)溶解,有机相用饱和碳酸氢钠溶液(15mL×3)洗涤,盐水(15mL)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用制备板分离得到N-(5-溴-2-环丙基-4-(2,4-二氟苯氧基)苯基)乙磺酰胺(0.07g,白色固体,产率69%)。5-Bromo-2-cyclopropyl-4-(2,4-difluorophenoxy)phenylamine (0.08 g, 0.24 mmol) and pyridine (0.037 g, 0.47 mmol) were dissolved in dichloromethane at room temperature. In 10 mL), ethylsulfonyl chloride (0.06 g, 0.47 mmol) was added dropwise to the reaction system, and the mixture was heated to 50 ° C for 4 hours. After completion of the reaction, the methylene chloride was evaporated to dryness. mjjjjjjjjjjjjjjjjjjjjjjjjj Drying, filtration, spin-drying, and the crude product was purified by preparative chromatography to give N-(5-bromo-2-cyclopropyl-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (0.07 g, White solid, yield 69%).
MS m/z(ESI):432.0,434.0[M+H] +. MS m/z (ESI): 432.0, 434.0 [M+H] + .
第五步:N-(2-环丙基-4-(2,4-二氟苯氧基)-5-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙磺酰胺Step 5: N-(2-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3- b]pyridin-4-yl)phenyl)ethanesulfonamide
Figure PCTCN2018073989-appb-000246
Figure PCTCN2018073989-appb-000246
室温下,将N-(5-溴-2-环丙基-4-(2,4-二氟苯氧基)苯基)乙磺酰胺(0.045g,0.10mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(0.045g,0.10mmol),碳酸钾(0.029g,0.20mmol)和[1,1'-双(二苯基 膦基)二茂铁]二氯化钯(0.01g,0.01mmol)溶解于二氧六环(4mL)和水(1mL)中,氮气置换三次,加热至90℃过夜,冷却至室温。反应液用乙酸乙酯(20mL)稀释,硅藻土过滤,硅藻土用乙酸乙酯洗涤(20mL),合并有机相,有机相用食盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤,旋干,粗产物用制备板分离得N-(2-环丙基-4-(2,4-二氟苯氧基)-5-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙磺酰胺(0.06g,无色油状物,产率:90%)。N-(5-Bromo-2-cyclopropyl-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (0.045 g, 0.10 mmol), 6-methyl-4 -(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine ( 0.045 g, 0.10 mmol), potassium carbonate (0.029 g, 0.20 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.01 g, 0.01 mmol) dissolved in dioxane Six rings (4 mL) and water (1 mL) were replaced with nitrogen three times, heated to 90 ° C overnight and cooled to room temperature. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. Filtration, spin-drying, and the crude product was isolated on a preparative plate to give N-(2-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-1-toluenesulfonyl-1H Pyrrolo[2,3-b]pyridin-4-yl)phenyl)ethanesulfonamide (0.06 g, colorless oil, yield: 90%).
MS m/z(ESI):638.2[M+H] +. MS m/z (ESI): 638.2 [M+H] + .
第六步:N-(2-环丙基-4-(2,4-二氟苯氧基)-5-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙磺酰胺Step 6: N-(2-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-1H-pyrrolo[2,3-b]pyridine-4- Phenyl)ethanesulfonamide
Figure PCTCN2018073989-appb-000247
Figure PCTCN2018073989-appb-000247
室温下,将N-(2-环丙基-4-(2,4-二氟苯氧基)-5-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙磺酰胺(0.03g,0.047mmol)溶解于乙醇(6mL)中,然后将甲醇钠(0.03g,0.047mmol)加入到反应液中,加热至50℃,反应14小时。反应结束后,在减压下将乙醇蒸干,残留物用乙酸乙酯(30mL)溶解,有机相用饱和食盐水(15mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用制备板分离(石油醚:乙酸乙酯=1:1,v/v)得到N-(2-环丙基-4-(2,4-二氟苯氧基)-5-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙磺酰胺(0.02g,无色油状物,产率:88%)。N-(2-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3- at room temperature b] Pyridin-4-yl)phenyl)ethanesulfonamide (0.03 g, 0.047 mmol) was dissolved in ethanol (6 mL), then sodium methoxide (0.03 g, 0.047 mmol) was added to the reaction mixture and heated to 50 ° C , the reaction was 14 hours. After the completion of the reaction, the ethanol was evaporated to dryness EtOAcjjjjjjjjjjjjjjjjj The crude product was separated with a preparative plate (petroleum ether: ethyl acetate = 1:1, v/v) to give N-(2-cyclopropyl-4-(2,4-difluorophenoxy)-5- ( 6-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)ethanesulfonamide (0.02 g, colorless oil, yield: 88%).
MS m/z(ESI):484.1[M+H] +. MS m/z (ESI): 484.1 [M+H] + .
第七步:4-(4-环丙基-2-(2,4-二氟苯氧基)-5-(乙基磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物Step 7: 4-(4-Cyclopropyl-2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl-1H-pyrrolo[ 2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000248
Figure PCTCN2018073989-appb-000248
冰浴下,将N-(2-环丙基-4-(2,4-二氟苯氧基)-5-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)乙磺酰胺(0.02g,0.04mmol)溶解于二氯甲烷(5mL)中,然后将间氯过氧苯甲酸(0.011g,0.06mmol)加入到反应液中,反应半小时。反应结束后,反应液用二氯甲烷(20mL)稀释,有机相用饱和碳酸氢钠溶液洗涤(10mL×3),食盐水(15mL)洗涤,有机相用无水硫酸钠干燥,过滤,旋干,粗产物用反相制备色 谱分离得到4-(4-环丙基-2-(2,4-二氟苯氧基)-5-(乙基磺酰氨基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(0.06g,淡黄色固体,产率29%)。N-(2-cyclopropyl-4-(2,4-difluorophenoxy)-5-(6-methyl-1H-pyrrolo[2,3-b]pyridine-4 under ice bath -yl)phenyl)ethanesulfonamide (0.02 g, 0.04 mmol) was dissolved in dichloromethane (5 mL), then m-chloroperoxybenzoic acid (0.011 g, 0.06 mmol) was added to the reaction mixture for half an hour. . After completion of the reaction, the reaction mixture was diluted with methylene chloride (20 mL). EtOAc (EtOAc m. The crude product was isolated by reverse phase preparative chromatography to give 4-(4-cyclopropyl-2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-6-methyl -1H-pyrrolo[2,3-b]pyridine-7-oxide (0.06 g, pale yellow solid, yield 29%).
MS m/z(ESI):500.1[M+H] +. MS m/z (ESI): 500.1 [M+H] + .
1H NMR(400MHz,CDCl 3):δ11.72(br,1H),7.63(s,1H),7.28(d,J=2.8Hz,1H),7.20(s,1H),7.08(s,1H),6.90-6.79(m,2H),6.75-6.70(m,1H),6.60-6.59(m,2H),3.23(q,J=7.2Hz,2H),2.68(s,3H),1.98-1.91(m,1H),1.44(t,J=7.2Hz,3H),1.06-1.02(m,2H),0.64-0.60(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ11.72 (br, 1H), 7.63 (s, 1H), 7.28 (d, J = 2.8Hz, 1H), 7.20 (s, 1H), 7.08 (s, 1H ), 6.90-6.79 (m, 2H), 6.75-6.70 (m, 1H), 6.60-6.59 (m, 2H), 3.23 (q, J = 7.2 Hz, 2H), 2.68 (s, 3H), 1.98- 1.91 (m, 1H), 1.44 (t, J = 7.2 Hz, 3H), 1.06-1.02 (m, 2H), 0.64-0.60 (m, 2H).
实施例96Example 96
4-(2-(4-溴-2-氟苯氧基)-5-((甲磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(4-Bromo-2-fluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide
Figure PCTCN2018073989-appb-000249
Figure PCTCN2018073989-appb-000249
第一步:4-氟-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯(甲)醛的制备First step: Preparation of 4-fluoro-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene (meth)aldehyde
Figure PCTCN2018073989-appb-000250
Figure PCTCN2018073989-appb-000250
3-溴-4-氟苯(甲)醛(1.34g,6.61mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(3.0g,7.28mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(386mg,0.52mmol),碳酸钾(1.82g,13.32mmol)溶于1,4-二氧六环(16mL),水(4mL),通氮气,在氮气保护下100℃反应4小时后反应完全。将反应液倒入水中(50mL),用乙酸乙酯萃取(50mL×2),合并有机相后用水洗(100mL),饱和食盐水洗(100mL),无水硫酸钠干燥,过滤浓缩后用柱层析(石油醚:乙酸乙酯=2:1)得到化合物4-氟-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯(甲)醛(2.1g,产率78%)。3-bromo-4-fluorobenzene(meth)aldehyde (1.34 g, 6.61 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro Cyclo-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (3.0 g, 7.28 mmol), [1,1'-bis(diphenylphosphino)ferrocene Palladium dichloride (386 mg, 0.52 mmol), potassium carbonate (1.82 g, 13.32 mmol) dissolved in 1,4-dioxane (16 mL), water (4 mL), EtOAc The reaction was complete after 4 hours. The reaction mixture was poured into water (50 mL), and extracted with ethyl acetate (50 mL×2), and the organic phase was combined, washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate Analysis (petroleum ether: ethyl acetate = 2:1) gave the compound 4-fluoro-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl) Phenyl (meth)aldehyde (2.1 g, yield 78%).
第二步:4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯(甲)醛的制备Second step: 4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene (meth)aldehyde preparation
Figure PCTCN2018073989-appb-000251
Figure PCTCN2018073989-appb-000251
4-氟-3-(6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)苯(甲)醛(1.0g,2.45mmol)溶于N-甲基吡咯烷酮(10mL)中,加入4-溴-2-氟苯酚(1.4g,7.35mmol),碳酸铯(2.39g,7.35mmol),在180℃微波反应30分钟后冷却至室温,加入水(20mL),然后用乙酸乙酯萃取(20mL×2),合并有机相后依次用水(40mL)和饱和食盐水(40mL)洗涤,并用无水硫酸钠干燥,浓缩后柱层析(石油醚:乙酸乙酯=1:1,V/V)得到4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯(甲)醛(330mg,产率32%)。4-Fluoro-3-(6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene(meth)aldehyde (1.0 g, 2.45 mmol) dissolved in N -Methylpyrrolidone (10 mL), 4-bromo-2-fluorophenol (1.4 g, 7.35 mmol), cesium carbonate (2.39 g, 7.35 mmol), microwaved at 180 ° C for 30 minutes, cooled to room temperature, added water (20 mL), then extracted with ethyl acetate (20 mL×2). The organic phase was washed with water (40 mL) and brine (40 mL) and dried over anhydrous sodium sulfate. Ethyl acetate = 1:1, V/V) gave 4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridine-4 -yl) phenyl (meth)aldehyde (330 mg, yield 32%).
第三步:(4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)甲醇的制备The third step: (4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)methanol preparation
Figure PCTCN2018073989-appb-000252
Figure PCTCN2018073989-appb-000252
4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯(甲)醛(330mg,0.77mmol)溶于甲醇(5mL)中,冰浴下加入硼氢化钠(59mg,1.56mmol),搅拌反应3小时,用饱和氯化铵水溶液(10mL)淬灭,加入水(20mL),然后用乙酸乙酯萃取(20mL×2),合并有机相后依次用水(40mL)和饱和食盐水(40mL)洗涤,并用无水硫酸钠干燥,过滤浓缩后用柱层析(石油醚:乙酸乙酯=1:1,V/V)得到(4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)甲醇(179mg,产率54%)。4-(4-Bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)benzene(methyl)aldehyde (330 mg, 0.77 mmol) Dissolved in methanol (5 mL), and added sodium borohydride (59 mg, 1.56 mmol), and the mixture was stirred for 3 hr, then quenched with saturated aqueous ammonium chloride (10 mL), water (20 mL) The organic phase was combined and washed with water (40 mL) and brine (40 mL) and dried over anhydrous sodium sulfate. 1,V/V) gives (4-(4-bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl Methanol (179 mg, yield 54%).
第四步:4-(2-(4-溴-2-氟苯氧基)-5-(溴甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Fourth step: 4-(2-(4-bromo-2-fluorophenoxy)-5-(bromomethyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine Preparation
Figure PCTCN2018073989-appb-000253
Figure PCTCN2018073989-appb-000253
(4-(4-溴-2-氟苯氧基)-3-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)苯基)甲醇(179mg,0.42mmol)溶于二氯甲烷(3mL)中,冰浴下加入三溴化磷(171mg,0.63mmol),搅拌至室温反应过夜,用碳酸钠的水溶液(1M)调反应液至中性,加入水(20mL),然后用二氯甲烷萃取(20mL×2),合并有机相后依次用水(40mL)和饱和食盐水(40mL)洗涤,并用无水硫酸钠干燥,浓缩后柱层析(石油醚:乙酸乙酯=2:1,V/V)得到4-(2-(4-溴-2-氟苯氧基)-5-(溴甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(130mg,产率63%)。(4-(4-Bromo-2-fluorophenoxy)-3-(6-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)phenyl)methanol (179 mg, 0.42 mmol Dissolved in dichloromethane (3 mL), added phosphorus tribromide (171 mg, 0.63 mmol) under ice bath, stirred at room temperature overnight, and the reaction solution was adjusted to neutral with sodium carbonate aqueous solution (1 M), and water was added. 20 mL), then extracted with dichloromethane (20 mL×2). The organic phase was combined, washed with water (40 mL) and brine (40 mL) and dried over anhydrous sodium sulfate. Ethyl ester = 2:1, V/V) gave 4-(2-(4-bromo-2-fluorophenoxy)-5-(bromomethyl)phenyl)-6-methyl-1H-pyrrole [2,3-b]pyridine (130 mg, yield 63%).
第五步:4-(2-(4-溴-2-氟苯氧基)-5-((甲硫基)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Step 5: 4-(2-(4-Bromo-2-fluorophenoxy)-5-((methylthio)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]Preparation of pyridine
Figure PCTCN2018073989-appb-000254
Figure PCTCN2018073989-appb-000254
4-(2-(4-溴-2-氟苯氧基)-5-(溴甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(130mg,0.26mmol)溶于N,N-二甲基甲酰胺(3mL)中,冰浴下加入甲硫醇钠(149mg,0.43mmol),搅拌至室温反应过夜,用氯化铵(10mL)的水溶液淬灭,加入水(20mL),然后用二氯甲烷萃取(20mL×2),合并有机相后依次用水(40mL)和饱和食盐水(40mL)洗涤,并用无水硫酸钠干燥,过滤浓缩后柱层析(石油醚:乙酸乙酯=2:1,V/V)得到4-(2-(4-溴-2-氟苯氧基)-5-((甲硫基)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(50mg,产率41%)。4-(2-(4-Bromo-2-fluorophenoxy)-5-(bromomethyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (130 mg, 0.26 Ethyl acetate (3 mL) was dissolved in EtOAc (3 mL). After adding water (20 mL), and then extracting with dichloromethane (20 mL × 2), the organic phase was combined, washed with water (40 mL) and brine (40 mL), and dried over anhydrous sodium sulfate (petroleum ether: ethyl acetate = 2:1, V/V) gave 4-(2-(4-bromo-2-fluorophenoxy)-5-((methylthio)methyl)phenyl)- 6-Methyl-1H-pyrrolo[2,3-b]pyridine (50 mg, yield 41%).
第六步:4-(2-(4-溴-2-氟苯氧基)-5-((甲磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 6: 4-(2-(4-Bromo-2-fluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]Preparation of pyridine-7-oxide
Figure PCTCN2018073989-appb-000255
Figure PCTCN2018073989-appb-000255
4-(2-(4-溴-2-氟苯氧基)-5-((甲硫基)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(50mg,0.11mmol)溶于THF(2mL)中,室温下加入间氯过氧苯甲酸(78mg,0.39mmol),室温下搅拌反应十分钟,用饱和氯化铵水溶液(10mL)淬灭,加入水(10mL),然后用乙酸乙酯萃取(10mL×2),合并有机相后依次用碳酸氢钠的水溶液洗(20mL),水(20mL)和饱和食盐水(20mL)洗涤,并用无水硫酸钠干燥,过滤浓缩后制备色谱得到4-(2-(4-溴-2-氟苯氧基)-5-((甲磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(20mg,产率36%)。4-(2-(4-Bromo-2-fluorophenoxy)-5-((methylthio)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (50 mg, 0.11 mmol) was dissolved in THF (2 mL), EtOAc (EtOAc (EtOAc,EtOAc) Water (10 mL), then extracted with ethyl acetate (10 mL×2), EtOAc (EtOAc) Drying with sodium, concentration by filtration and preparative chromatography to give 4-(2-(4-bromo-2-fluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrole And [2,3-b]pyridine-7-oxide (20 mg, yield 36%).
1H NMR(400MHz,DMSO-d 6):δ12.31(s,1H),7.61(s,2H),7.40(d,J=8.4Hz,1H),7.30(dd,J=16.7Hz,5.8Hz,2H),7.18(s,1H),7.09–6.91(m,2H),6.45(d,J=3.1Hz,1H),4.51(s,2H),2.90(s,3H),2.45(s,3H). 1 H NMR (400MHz, DMSO- d 6): δ12.31 (s, 1H), 7.61 (s, 2H), 7.40 (d, J = 8.4Hz, 1H), 7.30 (dd, J = 16.7Hz, 5.8 Hz, 2H), 7.18 (s, 1H), 7.09 - 6.91 (m, 2H), 6.45 (d, J = 3.1 Hz, 1H), 4.51 (s, 2H), 2.90 (s, 3H), 2.45 (s) , 3H).
MS m/z(ESI):505.1[M+H] +MS m/z (ESI): 505.1 [M+H] + .
实施例97Example 97
4-(2-(2,4-二氟苯氧基)-5-((乙基磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(2,4-difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-oxide
Figure PCTCN2018073989-appb-000256
Figure PCTCN2018073989-appb-000256
第一步:3-溴-4-(2,4-二氟苯氧基)苯甲醛的制备First step: Preparation of 3-bromo-4-(2,4-difluorophenoxy)benzaldehyde
Figure PCTCN2018073989-appb-000257
Figure PCTCN2018073989-appb-000257
100mL三口瓶中依次加入2,4-二氟苯酚(1.47g,11.33mmol),3-溴-4-氟苯甲醛(2.30g,11.33mmol),碳酸铯(4.05g,12.46mmol),二甲基亚砜(10mL)。油浴加热升温至100℃,反应1小时后冷却至室温,反应液用乙酸乙酯(30mL)稀释后用饱和食盐水洗涤(10mL×3),有机相经无水硫酸钠干燥,过滤,旋干。粗产物用柱层析分离(石油醚:乙酸乙酯=5:1,V/V)纯化得到3-溴-4-(2,4-二氟苯氧基)苯甲醛(2.60g,淡黄色油状物,产率73%)。In a 100 mL three-necked flask, 2,4-difluorophenol (1.47 g, 11.33 mmol), 3-bromo-4-fluorobenzaldehyde (2.30 g, 11.33 mmol), cesium carbonate (4.05 g, 12.46 mmol), dimethyl Sulfone (10 mL). The mixture was heated to 100 ° C in an oil bath, and the mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate (30 mL) and brine (10 mL×3). dry. The crude product was purified by column chromatography (EtOAc:EtOAc:EtOAc:EtOAc: Oil, yield 73%).
第二步:3-溴-4-(2,4-二氟苯氧基)苯甲醇的制备The second step: preparation of 3-bromo-4-(2,4-difluorophenoxy)benzyl alcohol
Figure PCTCN2018073989-appb-000258
Figure PCTCN2018073989-appb-000258
3-溴-4-(2,4-二氟苯氧基)苯甲醛(2.60g,8.31mmol)溶于甲醇(10mL)与四氢呋喃(10mL)混合溶剂中,室温下搅拌2-3分钟后,加入硼氢化钠(0.095g,2.49mmol),加毕室温条件下搅拌2小时,反应结束。将反应混合液旋干,残留物用乙酸乙酯(30mL)溶解,饱和食盐水(10mL×3)洗涤,有机相经无水硫酸钠干燥,过滤,旋干,得到粗产物3-溴-4-(2,4-二氟苯氧基)苯甲醇(2.6g,白色固体),直接用于下一步。3-bromo-4-(2,4-difluorophenoxy)benzaldehyde (2.60 g, 8.31 mmol) was dissolved in methanol (10 mL) and tetrahydrofuran (10 mL). Sodium borohydride (0.095 g, 2.49 mmol) was added, and the mixture was stirred at room temperature for 2 hours, and the reaction was completed. The reaction mixture was dried with EtOAc (3 mL). -(2,4-Difluorophenoxy)benzyl alcohol (2.6 g, white solid) was used directly in the next step.
第三步:2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯的制备The third step: preparation of 2-bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene
Figure PCTCN2018073989-appb-000259
Figure PCTCN2018073989-appb-000259
3-溴-4-(2,4-二氟苯氧基)苯甲醇(2.60g,8.25mmol)溶于二氯甲烷(20mL)中,冰浴冷却至0~5℃,滴加三溴化磷(2.46g,9.08mmol),加毕自然升温至室温,搅拌3小时反应结束。将反应液缓慢倒入冰水(50mL)中,滴加饱和碳酸钠溶液中和,分液,水相用二氯甲烷萃取(15mL×3),合并有机相,有机相用饱和食盐水(15mL×2)洗涤,无水硫酸钠干燥,过滤,旋干,得到2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯(2.60g,白色固体),直接用于下一步反应。3-Bromo-4-(2,4-difluorophenoxy)benzyl alcohol (2.60 g, 8.25 mmol) was dissolved in dichloromethane (20 mL), cooled to 0 to 5 ° C, and tribromide was added dropwise. Phosphorus (2.46 g, 9.08 mmol) was heated to room temperature after the addition, and the reaction was completed after stirring for 3 hours. The reaction solution was slowly poured into ice water (50 mL), neutralized with saturated sodium carbonate solution, and the mixture was separated, and the aqueous phase was extracted with dichloromethane (15 mL×3), and the organic phase was combined. ×2) Washed, dried over anhydrous sodium sulfate, filtered, and dried to give 2-bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene (2.60 g, white solid) , used directly in the next reaction.
第四步:3-溴-4-(2,4-二氟苯氧基)苄基乙基硫烷的制备Step 4: Preparation of 3-bromo-4-(2,4-difluorophenoxy)benzylethylsulfane
Figure PCTCN2018073989-appb-000260
Figure PCTCN2018073989-appb-000260
100mL三口瓶中依次加入2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯(2.40g,6.35mmol),乙硫醇钠(0.53g,6.35mmol),N,N-二甲基甲酰胺(40mL),室温搅拌4小时反应结束。反应液用乙酸乙酯(50mL)稀释,经饱和食盐水洗涤(10mL×5),有机相用无水硫酸钠干燥,过滤,旋干,柱层析分离(石油醚:乙酸乙酯=5:1,V/V)得到3-溴-4-(2,4-二氟苯氧基)苄基乙基硫烷(1.30g,油状物,收率57%)。2-Bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene (2.40 g, 6.35 mmol) and sodium ethanethiolate (0.53 g, 6.35 mmol) were sequentially added to a 100 mL three-necked flask. N,N-dimethylformamide (40 mL) was stirred at room temperature for 4 hours and the reaction was completed. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. 1, V/V) gave 3-bromo-4-(2,4-difluorophenoxy)benzylethylsulfane (1.30 g, oil, yield 57%).
第五步:2-溴-1-(2,4-二氟苯氧基)-4-((乙基磺酰)甲基)苯的制备Step 5: Preparation of 2-bromo-1-(2,4-difluorophenoxy)-4-((ethylsulfonyl)methyl)benzene
Figure PCTCN2018073989-appb-000261
Figure PCTCN2018073989-appb-000261
3-溴-4-(2,4-二氟苯氧基)苄基乙基硫烷(1.3g,3.6mmol)溶于二氯甲烷(20mL)中,室温下,加入间氯过氧苯甲酸(1.8g,9.0mmol),搅拌1小时,LC-MS检测反应完全,向反应溶液中加入饱和碳酸钠溶液(50mL),然后用乙酸乙酯萃取(50mL×2),合并有机相后用饱和氯化钠溶液(80mL×2)洗涤,无水硫酸钠干燥,减压浓缩得到2-溴-1-(2,4-二氟苯氧基)-4-((乙基磺酰)甲基)苯(1.3g,92%)。MS m/z(ESI):391.2,393.2[M+H] +. 3-Bromo-4-(2,4-difluorophenoxy)benzylethylsulfane (1.3 g, 3.6 mmol) was dissolved in dichloromethane (20 mL), and m-chloroperoxybenzoic acid was added at room temperature. (1.8g, 9.0mmol), stirred for 1 hour, the reaction was completed by LC-MS. A saturated sodium carbonate solution (50 mL) was added to the reaction solution, and then extracted with ethyl acetate (50 mL×2), and the organic phase was combined and saturated. The solution was washed with sodium chloride solution (80 mL×2), dried over anhydrous sodium sulfate Benzene (1.3 g, 92%). MS m/z (ESI): 391.2, 393.2 [M+H] + .
第五步:4-(2-(2,4-二氟苯氧基)-5-((乙基磺酰)甲基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备The fifth step: 4-(2-(2,4-difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1-toluenesulfonyl-1H- Preparation of pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000262
Figure PCTCN2018073989-appb-000262
将2-溴-1-(2,4-二氟苯氧基)-4-((乙基磺酰)甲基)苯(100mg,0.26mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(210mg,0.51mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(18.6mg,0.03mmol),碳酸钾(70.6mg,0.51mmol)溶于1,4-二氧六环(10mL)和水(3mL),置换氮气,加热到100℃搅拌4小时,LC/MS检测反应完全。向反应液中加入水(50mL),用乙酸乙酯(50mL)萃取,有机相用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=1:1,V/V)得4-(2-(2,4-二氟苯氧基)-5-((乙基磺酰)甲基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(150mg,纯度70%,产率68%)。2-Bromo-1-(2,4-difluorophenoxy)-4-((ethylsulfonyl)methyl)benzene (100 mg, 0.26 mmol), 6-methyl-4-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (210 mg, 0.51 mmol) , [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (18.6 mg, 0.03 mmol), potassium carbonate (70.6 mg, 0.51 mmol) dissolved in 1,4-dioxane (10 mL) and water (3 mL) were replaced with nitrogen and heated to 100 ° C for 4 hours. The reaction was confirmed by LC/MS. Water (50 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (50 mL). Ethyl ester = 1:1, V / V) gave 4-(2-(2,4-difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl- 1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (150 mg, purity 70%, yield 68%).
MS m/z(ESI):597.1[M+H] + MS m/z (ESI): 597.1 [M+H] +
第六步:4-(2-(2,4-二氟苯氧基)-5-((乙基磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b] 吡啶的制备Step 6: 4-(2-(2,4-Difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b] Preparation of pyridine
Figure PCTCN2018073989-appb-000263
Figure PCTCN2018073989-appb-000263
将4-(2-(2,4-二氟苯氧基)-5-((乙基磺酰)甲基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(150mg,纯度70%,0.25mmol)溶于叔丁醇(10mL),将氢氧化钾水溶液(3M,5mL)加入上述溶液中,加热到55℃搅拌过夜。冷却至室温后向反应液中加乙酸乙酯(50mL)稀释,用饱和食盐水(50mL×2)洗涤,用无水硫酸钠干燥,浓缩后用硅胶制备板分离纯化(二氯甲烷:甲醇=10:1,V/V)得4-(2-(2,4-二氟苯氧基)-5-((乙基磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(40mg,产率51.0%).4-(2-(2,4-Difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[ 2,3-b]pyridine (150 mg, purity 70%, 0.25 mmol) was dissolved in tert-butanol (10 mL), and aqueous potassium hydroxide (3M, 5 mL) was added to the above solution, and the mixture was stirred at 55 ° C overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, and evaporated. 10:1, V/V) gave 4-(2-(2,4-difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrole And [2,3-b]pyridine (40 mg, yield 51.0%).
MS m/z(ESI):443.1[M+H] + MS m/z (ESI): 443.1 [M+H] +
第七步:4-(2-(2,4-二氟苯氧基)-5-((乙基磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 7: 4-(2-(2,4-Difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]Preparation of pyridine-7-oxide
Figure PCTCN2018073989-appb-000264
Figure PCTCN2018073989-appb-000264
将4-(2-(2,4-二氟苯氧基)-5-((乙基磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(40mg,0.09mmol)溶于四氢呋喃(2mL),加入间氯过氧苯甲酸(28mg,0.14mmol),室温搅拌30分钟。向反应液中加入乙酸乙酯(50mL),用饱和碳酸钠溶液(30mL×2)洗涤,然后用饱和食盐水(30mL)洗涤,用无水硫酸钠干燥,浓缩后通过硅胶制备色谱分离纯化得到4-(2-(2,4-二氟苯氧基)-5-((乙基磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(13.0mg,产率31%)。4-(2-(2,4-Difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Pyridine (40 mg, 0.09 mmol) was dissolved in tetrahydrofuran (2 mL). m. Ethyl acetate (50 mL) was added to the mixture, and the mixture was washed with saturated aqueous sodium sulfate (30 mL) 4-(2-(2,4-difluorophenoxy)-5-((ethylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine -7-Oxide (13.0 mg, yield 31%).
1H NMR(400MHz,CDCl 3):δ12.48(s,1H),7.68(s,1H),7.47-7.43(m,3H),7.08–7.06(m,1H),7.01-6.96(m,1H),6.91-6.84(m,2H),6.78(s,1H),4.31(s,2H),3.07-3.05(q,J=5.6Hz,2H),2.94(s,3H),1.27-1.25(t,J=7.2Hz,3H). 1 H NMR (400MHz, CDCl 3 ): δ12.48 (s, 1H), 7.68 (s, 1H), 7.47-7.43 (m, 3H), 7.08-7.06 (m, 1H), 7.01-6.96 (m, 1H), 6.91-6.84 (m, 2H), 6.78 (s, 1H), 4.31 (s, 2H), 3.07-3.05 (q, J = 5.6 Hz, 2H), 2.94 (s, 3H), 1.27-1.25 (t, J = 7.2 Hz, 3H).
MS m/z(ESI)=459.1[M+H] + MS m/z (ESI) = 459.1 [M+H] +
实施例98Example 98
4-(2-(2,4-二氟苯氧基)-5-(2-(乙基磺酰)丙烷-2-基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000265
Figure PCTCN2018073989-appb-000265
第一步:2-溴-1-(2,4-二氟苯氧基)-4-(2-(乙基磺酰)丙烷-2-基)苯的制备First step: Preparation of 2-bromo-1-(2,4-difluorophenoxy)-4-(2-(ethylsulfonyl)propan-2-yl)benzene
Figure PCTCN2018073989-appb-000266
Figure PCTCN2018073989-appb-000266
将2-溴-1-(2,4-二氟苯氧基)-4-((乙基磺酰)甲基)苯(469mg,1.2mmol)溶于四氢呋喃(10mL),冷却至0℃,加入氢化钠(60%,240mg,6mmol),搅拌10分钟,加入碘甲烷(0.75mL,12mmol),室温下搅拌过夜。向反应液中加入饱乙酸乙酯(80mL),用饱和食盐水(50mL×2)洗涤,用无水硫酸钠干燥,浓缩后通过硅胶制备色谱分离纯化得到2-溴-1-(2,4-二氟苯氧基)-4-(2-(乙基磺酰)丙烷-2-基)苯(400mg,产率80%)。2-Bromo-1-(2,4-difluorophenoxy)-4-((ethylsulfonyl)methyl)benzene (469 mg, 1.2 mmol) was dissolved in tetrahydrofuran (10 mL) and cooled to 0. Sodium hydride (60%, 240 mg, 6 mmol) was added and stirred for 10 min. Ethyl acetate (80 mL) was added to the reaction mixture, which was washed with saturated brine (50 mL×2) and dried over anhydrous sodium sulfate. -Difluorophenoxy)-4-(2-(ethylsulfonyl)propan-2-yl)benzene (400 mg, yield 80%).
1H NMR(400MHz,DMSO-d 6):δ7.88(d,J=2.4Hz,1H),7.58-7.50(m,2H),7.31–7.25(m,1H),7.18-7.13(m,1H),6.90(d,J=8.8Hz,1H),6.78(s,1H),2.91-2.85(q,J=7.6Hz,2H),1.76(s,6H),1.08-1.05(t,J=6.4Hz,3H). 1 H NMR (400MHz, DMSO- d 6): δ7.88 (d, J = 2.4Hz, 1H), 7.58-7.50 (m, 2H), 7.31-7.25 (m, 1H), 7.18-7.13 (m, 1H), 6.90 (d, J = 8.8 Hz, 1H), 6.78 (s, 1H), 2.91-2.85 (q, J = 7.6 Hz, 2H), 1.76 (s, 6H), 1.08-1.05 (t, J =6.4Hz, 3H).
MS m/z(ESI):419.2,421.2[M+H] + MS m/z (ESI): 419.2, 421.2 [M+H] +
第二步:4-(2-(2,4-二氟苯氧基)-5-(2-(乙基磺酰)丙烷-2-基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备Second step: 4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1-toluene Preparation of sulfonyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000267
Figure PCTCN2018073989-appb-000267
以2-溴-1-(2,4-二氟苯氧基)-4-(2-(乙基磺酰)丙烷-2-基)苯为原料,参照实施例九十七第五步,得4-(2-(2,4-二氟苯氧基)-5-(2-(乙基磺酰)丙烷-2-基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(250mg,产率55%)。Taking 2-bromo-1-(2,4-difluorophenoxy)-4-(2-(ethylsulfonyl)propan-2-yl)benzene as a raw material, refer to the fifth step of the ninety-seventh step of the embodiment. 4-(2-(2,4-Difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1-toluenesulfonyl- 1H-pyrrolo[2,3-b]pyridine (250 mg, yield 55%).
MS m/z(ESI)=625.1[M+H] + MS m/z (ESI) = 625.1 [M+H] +
第三步:4-(2-(2,4-二氟苯氧基)-5-(2-(乙基磺酰)丙烷-2-基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Third step: 4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine
Figure PCTCN2018073989-appb-000268
Figure PCTCN2018073989-appb-000268
以4-(2-(2,4-二氟苯氧基)-5-(2-(乙基磺酰)丙烷-2-基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶为原料,参照实施例九十七第六步,得4-(2-(2,4-二氟苯氧基)-5-(2-(乙基磺酰)丙烷-2-基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(150mg,产率80%)。4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1-toluenesulfonyl- 1H-pyrrolo[2,3-b]pyridine is used as a raw material, and the sixth step of the seventy-seventh step of the embodiment is given to obtain 4-(2-(2,4-difluorophenoxy)-5-(2-(B) Sulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (150 mg, yield 80%).
MS m/z(ESI):471.1[M+H] + MS m/z (ESI): 471.1 [M+H] +
第四步:4-(2-(2,4-二氟苯氧基)-5-(2-(乙基磺酰)丙烷-2-基)苯基)-6-甲基-1H-吡咯 并[2,3-b]吡啶-7-氧化物的制备Fourth step: 4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000269
Figure PCTCN2018073989-appb-000269
以4-(2-(2,4-二氟苯氧基)-5-(2-(乙基磺酰)丙烷-2-基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶为原料,参照实施例九十七第七步,得4-(2-(2,4-二氟苯氧基)-5-(2-(乙基磺酰)丙烷-2-基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(32.4mg,产率33.3%)。4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2 , 3-b]pyridine as a raw material, referring to the seventh step of the seventy-seventh step of the example, 4-(2-(2,4-difluorophenoxy)-5-(2-(ethylsulfonyl)propane- 2-yl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (32.4 mg, yield 33.3%).
MS m/z(ESI):487.1[M+H] + MS m/z (ESI): 487.1 [M+H] +
1H NMR(400MHz,CDCl 3):δ12.35(s,1H),7.84(d,J=2.4Hz,1H),7.59-7.56(dd,J=8.8Hz,2.4Hz,1H),7.36-7.35(d,J=3.6Hz,1H),7.27(s,1H),7.04–6.91(m,2H),6.86-6.81(m,2H),6.60(d,J=3.2Hz,1H),2.80-2.75(m,5H),1.87(s,6H),1.30-1.26(t,J=7.2Hz,3H)。 1 H NMR (400MHz, CDCl 3 ): δ12.35 (s, 1H), 7.84 (d, J = 2.4Hz, 1H), 7.59-7.56 (dd, J = 8.8Hz, 2.4Hz, 1H), 7.36- 7.35 (d, J = 3.6 Hz, 1H), 7.27 (s, 1H), 7.04 - 6.91 (m, 2H), 6.86 - 6.81 (m, 2H), 6.60 (d, J = 3.2 Hz, 1H), 2.80 -2.75 (m, 5H), 1.87 (s, 6H), 1.30-1.26 (t, J = 7.2 Hz, 3H).
实施例99Example 99
4-(2-(2,4-二氟苯氧基)-5-((甲磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(2,4-Difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine- 7-oxide
Figure PCTCN2018073989-appb-000270
Figure PCTCN2018073989-appb-000270
第一步:(3-溴-4-(2,4-二氟苯氧基)苯甲基)(甲基)硫烷的制备First step: Preparation of (3-bromo-4-(2,4-difluorophenoxy)benzyl)(methyl)sulfane
Figure PCTCN2018073989-appb-000271
Figure PCTCN2018073989-appb-000271
100mL三口瓶中依次加入2-溴-4-(溴甲基)-1-(2,4-二氟苯氧基)苯(2.00g,5.29mmol),甲硫醇钠(0.45g,6.35mmol),N,N-二甲基甲酰胺(35mL),室温搅拌3小时反应结束。反应液用乙酸乙酯(80mL)稀释,经饱和食盐水洗涤(50mL×5),有机相用无水硫酸钠干燥,过滤,旋干,柱层析分离(石油醚:乙酸乙酯=5:1)得到(3-溴-4-(2,4-二氟苯氧基)苯甲基)(甲基)硫烷(1.00g,油状物,产率55%)。2-Bromo-4-(bromomethyl)-1-(2,4-difluorophenoxy)benzene (2.00 g, 5.29 mmol), sodium methanethiolate (0.45 g, 6.35 mmol) was sequentially added to a 100 mL three-necked flask. N,N-dimethylformamide (35 mL) was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. 1) (3-Bromo-4-(2,4-difluorophenoxy)benzyl)(methyl)sulfane (1.00 g, oil, yield 55%).
第二步:2-溴-1-(2,4-二氟苯氧基)-4-((甲磺酰)甲基)苯的制备Second step: Preparation of 2-bromo-1-(2,4-difluorophenoxy)-4-((methanesulfonyl)methyl)benzene
Figure PCTCN2018073989-appb-000272
Figure PCTCN2018073989-appb-000272
(3-溴-4-(2,4-二氟苯氧基)苯甲基)(甲基)硫烷(1.00g,2.90mmol)溶于二氯甲 烷(20mL)中,室温下,加入间氯过氧苯甲酸(1.76g,8.70mmol),搅拌1小时,LC-MS监测反应完全,向反应溶液中加入饱和碳酸钠溶液(50mL),然后用乙酸乙酯萃取(50mL×2),混合有机相,用饱和氯化钠溶液(80mL×2)洗涤,无水硫酸钠干燥,减压浓缩得到2-溴-1-(2,4-二氟苯氧基)-4-((甲磺酰)甲基)苯(1.0g,产率92%)。(3-Bromo-4-(2,4-difluorophenoxy)benzyl)(methyl)sulfane (1.00 g, 2.90 mmol) was dissolved in dichloromethane (20 mL). Chloroperoxybenzoic acid (1.76 g, 8.70 mmol), stirred for 1 hour, the reaction was completed by LC-MS, and saturated sodium carbonate solution (50 mL) was added to the reaction solution, then extracted with ethyl acetate (50 mL×2), and mixed. The organic phase was washed with a saturated aqueous sodium chloride solution (yield: EtOAc, EtOAc) Acyl)methyl)benzene (1.0 g, yield 92%).
MS m/z(ESI):377.2,379.2[M+H] +. MS m/z (ESI): 377.2, 379.2 [M+H] + .
第三步:4-(2-(2,4-二氟苯氧基)-5-((甲磺酰)甲基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备Third step: 4-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrole Preparation of [2,3-b]pyridine
Figure PCTCN2018073989-appb-000273
Figure PCTCN2018073989-appb-000273
将2-溴-1-(2,4-二氟苯氧基)-4-((甲磺酰)甲基)苯(110mg,0.29mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(190mg,0.35mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(22.0mg,0.03mmol),碳酸钾(82.0mg,0.60mmol)溶于1,4-二氧六环(10mL)和水(3mL),置换氮气,加热到100℃搅拌4小时,LC/MS检测反应完全。向反应液中加入水(50mL),用乙酸乙酯(50mL)萃取,有机相用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=1:1)得4-(2-(2,4-二氟苯氧基)-5-((甲磺酰)甲基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(130mg,产率77.0%)。2-Bromo-1-(2,4-difluorophenoxy)-4-((methylsulfonyl)methyl)benzene (110 mg, 0.29 mmol), 6-methyl-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (190 mg, 0.35 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22.0 mg, 0.03 mmol), potassium carbonate (82.0 mg, 0.60 mmol) dissolved in 1,4-dioxane ( 10 mL) and water (3 mL) were replaced with nitrogen, heated to 100 ° C for 4 hours, and the reaction was confirmed by LC/MS. Water (50 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (50 mL). Ethyl ester = 1:1) gave 4-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-toluenesulfonyl -1H-pyrrolo[2,3-b]pyridine (130 mg, yield 77.0%).
MS m/z(ESI):583.1[M+H] + MS m/z (ESI): 583.1 [M+H] +
第四步:4-(2-(2,4-二氟苯氧基)-5-((甲磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Fourth step: 4-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b] Preparation of pyridine
Figure PCTCN2018073989-appb-000274
Figure PCTCN2018073989-appb-000274
将4-(2-(2,4-二氟苯氧基)-5-((甲磺酰)甲基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(130mg,0.22mmol)溶于叔丁醇(15mL),将氢氧化钾水溶液(3M,8mL)加入上述溶液中,加热到75℃搅拌过夜。向反应液中加乙酸乙酯(50mL),用饱和食盐水(50mL×2)洗涤,用无水硫酸钠干燥,浓缩后用硅胶制备板分离纯化(二氯甲烷:甲醇=10:1)得4-(2-(2,4-二氟苯氧基)-5-((甲磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(60mg,产率63%).4-(2-(2,4-Difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2 3-B]pyridine (130 mg, 0.22 mmol) was dissolved in tert-butanol (15 mL). EtOAc (3M, EtOAc) Ethyl acetate (50 mL) was added to the mixture, and washed with brine (50 mL×2) and dried over anhydrous sodium sulfate. 4-(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine ( 60mg, yield 63%).
MS m/z(ESI):429.1[M+H] + MS m/z (ESI): 429.1 [M+H] +
第五步:4-(2-(2,4-二氟苯氧基)-5-((甲磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 5: 4-(2-(2,4-Difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3- b] Preparation of pyridine-7-oxide
Figure PCTCN2018073989-appb-000275
Figure PCTCN2018073989-appb-000275
将4-(2-(2,4-二氟苯氧基)-5-((甲磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(60mg,0.14mmol)溶于四氢呋喃(2mL),加入间氯过氧苯甲酸(57mg,0.28mmol),室温搅拌30分钟。向反应液中加入乙酸乙酯(50mL),用饱和碳酸钠溶液(30mL×2)洗涤,然后用饱和食盐水(30mL)洗涤,用无水硫酸钠干燥,浓缩后通过硅胶制备色谱分离纯化4-(2-(2,4-二氟苯氧基)-5-((甲磺酰)甲基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(13.0mg,产率:21%)。4-(2-(2,4-Difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (60 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 mL). m. Ethyl acetate (50 mL) was added to the mixture, and the mixture was washed with saturated aqueous sodium sulfate (30 mL×2), and then washed with brine (30 mL) -(2-(2,4-difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine-7 - Oxide (13.0 mg, yield: 21%).
1H NMR(400MHz,CDCl 3):δ12.24(s,1H),7.64(d,J=2.0Hz,1H),7.39-7.36(dd,J=8.4Hz,2.4Hz,1H),7.35(d,J=3.2Hz,1H),7.26(s,1H),7.04–6.91(m,2H),6.86-6.81(m,2H),6.60(d,J=3.2Hz,1H),4.28(s,2H),2.88(s,3H),2.75(s,3H)。 1 H NMR (400MHz, CDCl 3 ): δ12.24 (s, 1H), 7.64 (d, J = 2.0Hz, 1H), 7.39-7.36 (dd, J = 8.4Hz, 2.4Hz, 1H), 7.35 ( d, J = 3.2 Hz, 1H), 7.26 (s, 1H), 7.04 - 6.91 (m, 2H), 6.86 - 6.81 (m, 2H), 6.60 (d, J = 3.2 Hz, 1H), 4.28 (s) , 2H), 2.88 (s, 3H), 2.75 (s, 3H).
MS m/z(ESI):445.1[M+H] + MS m/z (ESI): 445.1 [M+H] +
实施例100Example 100
4-(2-(2,4-二氟苯氧基)-5-(2-(甲磺酰)丙烷-2-基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(2,4-difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000276
Figure PCTCN2018073989-appb-000276
第一步:2-溴-1-(2,4-二氟苯氧基)-4-(2-(甲磺酰)丙烷-2-基)苯和2-溴-1-(2,4-二氟苯氧基)-4-(1-(甲磺酰)乙基)苯的制备First step: 2-bromo-1-(2,4-difluorophenoxy)-4-(2-(methylsulfonyl)propan-2-yl)benzene and 2-bromo-1-(2,4 Of -difluorophenoxy)-4-(1-(methylsulfonyl)ethyl)benzene
Figure PCTCN2018073989-appb-000277
Figure PCTCN2018073989-appb-000277
将2-溴-1-(2,4-二氟苯氧基)-4-((甲磺酰)甲基)苯(300mg,0.80mmol)溶于四氢呋喃(10mL),冷却至0℃,加入氢化钠(60%,160mg,6mmol),搅拌10分钟,加入碘甲烷(1mL,16mmol),室温下搅拌过夜。向反应液中加入饱乙酸乙酯(80mL),用饱和食盐水(50mL×2)洗涤,用无水硫酸钠干燥,浓缩后通过硅胶制备色谱分离纯化得到2-溴-1-(2,4-二氟苯氧基)-4-(2-(甲磺酰)丙烷-2-基)苯(150mg,产率48%)和2-溴-1-(2,4-二氟苯氧基)-4-(1-(甲磺酰)乙基)苯(100mg,产率31%)。2-Bromo-1-(2,4-difluorophenoxy)-4-((methylsulfonyl)methyl)benzene (300 mg, 0.80 mmol) was dissolved in tetrahydrofuran (10 mL), cooled to 0 ° C, Sodium hydride (60%, 160 mg, 6 mmol) was stirred for 10 min. Ethyl acetate (80 mL) was added to the reaction mixture, which was washed with saturated brine (50 mL×2) and dried over anhydrous sodium sulfate. -difluorophenoxy)-4-(2-(methylsulfonyl)propan-2-yl)benzene (150 mg, yield 48%) and 2-bromo-1-(2,4-difluorophenoxy) 4-(1-(Methanesulfonyl)ethyl)benzene (100 mg, yield 31%).
2-溴-1-(2,4-二氟苯氧基)-4-(2-(甲磺酰)丙烷-2-基)苯:2-bromo-1-(2,4-difluorophenoxy)-4-(2-(methylsulfonyl)propan-2-yl)benzene:
1H NMR(400MHz,CDCl 3):δ7.85(d,J=2.4Hz,1H),7.52-7.49(dd,J=8.4Hz,2.4Hz,1H),7.16–7.06(m,1H),7.01-6.95(m,1H),6.92-6.87(m,1H),6.72(d,J=8.4Hz,1H),2.59(s,3H),1.82(s,6H). 1 H NMR (400MHz, CDCl 3 ): δ7.85 (d, J = 2.4Hz, 1H), 7.52-7.49 (dd, J = 8.4Hz, 2.4Hz, 1H), 7.16-7.06 (m, 1H), 7.01-6.95 (m, 1H), 6.92-6.87 (m, 1H), 6.72 (d, J = 8.4 Hz, 1H), 2.59 (s, 3H), 1.82 (s, 6H).
2-溴-1-(2,4-二氟苯氧基)-4-(1-(甲磺酰)乙基)苯:2-bromo-1-(2,4-difluorophenoxy)-4-(1-(methylsulfonyl)ethyl)benzene:
1H NMR(400MHz,CDCl 3):δ7.62(d,J=2.0Hz,1H),7.24-7.22(dd,J=8.4Hz,2.4Hz,1H),7.02–6.97(m,1H),6.93-6.88(m,1H),6.84-6.82(m,1H),6.67(d,J=8.4Hz,1H),4.10-4.07(q,J=7.2Hz,1H),2.64(s,3H),1.70-1.68(d,J=7.2Hz,3H). 1 H NMR (400 MHz, CDCl 3 ): δ 7.62 (d, J = 2.0 Hz, 1H), 7.24 - 7.22 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 7.02 - 6.97 (m, 1H), 6.93-6.88 (m, 1H), 6.84-6.82 (m, 1H), 6.67 (d, J = 8.4 Hz, 1H), 4.10-4.07 (q, J = 7.2 Hz, 1H), 2.64 (s, 3H) , 1.70-1.68 (d, J = 7.2 Hz, 3H).
第二步:4-(2-(2,4-二氟苯氧基)-5-(2-(甲磺酰)丙烷-2-基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备Second step: 4-(2-(2,4-difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1-toluene Preparation of acyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000278
Figure PCTCN2018073989-appb-000278
将2-溴-1-(2,4-二氟苯氧基)-4-(2-(甲磺酰)丙烷-2-基)苯(120mg,0.30mmol),6-甲基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(200mg,0.36mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(22.0mg,0.03mmol),碳酸钾(82.0mg,0.60mmol)溶于1,4-二氧六环(6mL)和水(2mL),置换氮气,加热到100℃搅拌过夜,LC/MS检测反应完全。向反应液中加入水(50mL),用乙酸乙酯(50mL)萃取,有机相用饱和食盐水(50mL)洗涤,用无水硫酸钠干燥,浓缩后用硅胶柱色谱分离纯化(石油醚:乙酸乙酯=1:1)得4-(2-(2,4-二氟苯氧基)-5-(2-(甲磺酰)丙烷-2-基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(120mg,产率66%)。2-Bromo-1-(2,4-difluorophenoxy)-4-(2-(methylsulfonyl)propan-2-yl)benzene (120 mg, 0.30 mmol), 6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (200mg , 0.36 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (22.0 mg, 0.03 mmol), potassium carbonate (82.0 mg, 0.60 mmol) dissolved in 1,4- Dioxane (6 mL) and water (2 mL) were replaced with nitrogen and heated to 100 ° C overnight. The reaction was completed by LC/MS. Water (50 mL) was added to the reaction mixture, and the mixture was washed with ethyl acetate (50 mL). Ethyl ester = 1:1) 4-(2-(2,4-difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl- 1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (120 mg, yield 66%).
MS m/z(ESI):611.1[M+H] + MS m/z (ESI): 611.1 [M+H] +
第三步:4-(2-(2,4-二氟苯氧基)-5-(2-(甲磺酰)丙烷-2-基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Third step: 4-(2-(2,4-difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrole Preparation of [2,3-b]pyridine
Figure PCTCN2018073989-appb-000279
Figure PCTCN2018073989-appb-000279
将4-(2-(2,4-二氟苯氧基)-5-(2-(甲磺酰)丙烷-2-基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(120mg,0.20mmol)溶于叔丁醇(15mL),将氢氧化钾溶液(3M,8mL)加入上述溶液中,加热到75℃搅拌过夜。向反应液中加乙酸乙酯(50mL)萃取,有机相用饱和食盐水(50mL×2)洗涤,用无水硫酸钠干燥,浓缩得4-(2-(2,4-二氟苯氧基)-5-(2-(甲磺酰)丙烷-2-基)苯基)-6-甲基-1H-吡咯并 [2,3-b]吡啶(80mg,产率89%).4-(2-(2,4-Difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1-toluenesulfonyl-1H - Pyrrolo[2,3-b]pyridine (120 mg, 0.20 mmol) was dissolved in tert-butanol (15 mL), and potassium hydroxide solution (3M, 8 mL) was added to the above solution and heated to 75 ° C overnight. The reaction mixture was extracted with ethyl acetate (50 mL). EtOAcjjjjjjjj -5-(2-(Methanesulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (80 mg, yield 89%).
MS m/z(ESI):457.1[M+H] + MS m/z (ESI): 457.1 [M+H] +
第四步:4-(2-(2,4-二氟苯氧基)-5-(2-(甲磺酰)丙烷-2-基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物Fourth step: 4-(2-(2,4-difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrole [2,3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000280
Figure PCTCN2018073989-appb-000280
将4-(2-(2,4-二氟苯氧基)-5-(2-(甲磺酰)丙烷-2-基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(80mg,0.17mmol)溶于四氢呋喃(5mL),加入间氯过氧苯甲酸(55mg,0.26mmol),室温搅拌30分钟。向反应液中加入乙酸乙酯(50mL),用饱和碳酸钠溶液(30mL×2)洗涤,然后用饱和食盐水(30mL)洗涤,用无水硫酸钠干燥,浓缩后通过硅胶制备色谱分离纯化得4-(2-(2,4-二氟苯氧基)-5-(2-(甲磺酰)丙烷-2-基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(20.0mg,产率24%)。 1H NMR(400MHz,CDCl 3):δ12.21(s,1H),7.85(d,J=2.8Hz,1H),7.59-7.56(dd,J=8.8Hz,2.8Hz,1H),7.37(d,J=3.6Hz,1H),7.28(s,1H),7.04–6.92(m,2H),6.87-6.82(m,2H),6.61(d,J=3.2Hz,1H),2.76(s,3H),2.67(s,3H),1.88(s,6H)。 4-(2-(2,4-Difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2, 3-b]pyridine (80 mg, 0.17 mmol) was dissolved in tetrahydrofuran (5 mL). m. Ethyl acetate (50 mL) was added to the reaction mixture, and the mixture was washed with saturated aqueous sodium sulfate (30 mL? 4-(2-(2,4-difluorophenoxy)-5-(2-(methylsulfonyl)propan-2-yl)phenyl)-6-methyl-1H-pyrrolo[2,3 -b]pyridine-7-oxide (20.0 mg, yield 24%). 1 H NMR (400 MHz, CDCl 3 ): δ 12.21. (s, 1H), 7.85 (d, J = 2.8 Hz, 1H), 7.59-7.56 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.37 ( d, J = 3.6 Hz, 1H), 7.28 (s, 1H), 7.04 - 6.92 (m, 2H), 6.87 - 6.82 (m, 2H), 6.61 (d, J = 3.2 Hz, 1H), 2.76 (s) , 3H), 2.67 (s, 3H), 1.88 (s, 6H).
MS m/z(ESI):473.1[M+H] + MS m/z (ESI): 473.1 [M+H] +
实施例101Example 101
4-(2-(2,4-二氟苯氧基)-5-(1-(甲磺酰)乙基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物4-(2-(2,4-Difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b] Pyridine-7-oxide
Figure PCTCN2018073989-appb-000281
Figure PCTCN2018073989-appb-000281
第一步:4-(2-(2,4-二氟苯氧基)-5-(1-(甲磺酰)乙基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备First step: 4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1-toluenesulfonyl-1H -Preparation of pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000282
Figure PCTCN2018073989-appb-000282
以2-溴-1-(2,4-二氟苯氧基)-4-(1-(甲磺酰)乙基)苯为原料,参照实施例一百第二步,得4-(2-(2,4-二氟苯氧基)-5-(1-(甲磺酰)乙基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(80mg,产率52.4%)。Taking 2-bromo-1-(2,4-difluorophenoxy)-4-(1-(methylsulfonyl)ethyl)benzene as a raw material, referring to the second step of the first embodiment, 4-(2) -(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrolo[2,3- b] pyridine (80 mg, yield 52.4%).
MS m/z(ESI):597.1[M+H] + MS m/z (ESI): 597.1 [M+H] +
第二步:4-(2-(2,4-二氟苯氧基)-5-(1-(甲磺酰)乙基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶的制备Second step: 4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1H-pyrrolo[2, Preparation of 3-b]pyridine
Figure PCTCN2018073989-appb-000283
Figure PCTCN2018073989-appb-000283
以4-(2-(2,4-二氟苯氧基)-5-(1-(甲磺酰)乙基)苯基)-6-甲基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶为原料,参照实施例二十三第三步,得4-(2-(2,4-二氟苯氧基)-5-(1-(甲磺酰)乙基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶(50mg,产率84.4%)。4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1-toluenesulfonyl-1H-pyrrole [2,3-b]pyridine as a raw material, referring to the third step of the twenty-third step of the example, 4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl) Phenyl)-6-methyl-1H-pyrrolo[2,3-b]pyridine (50 mg, yield 84.4%).
MS m/z(ESI):443.1[M+H] + MS m/z (ESI): 443.1 [M+H] +
第三步:4-(2-(2,4-二氟苯氧基)-5-(1-(甲磺酰)乙基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备The third step: 4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1H-pyrrolo[2, Preparation of 3-b]pyridine-7-oxide
Figure PCTCN2018073989-appb-000284
Figure PCTCN2018073989-appb-000284
以4-(2-(2,4-二氟苯氧基)-5-(1-(甲磺酰)乙基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶为原料,参照实施例一百第四步,得4-(2-(2,4-二氟苯氧基)-5-(1-(甲磺酰)乙基)苯基)-6-甲基-1H-吡咯并[2,3-b]吡啶-7-氧化物(18.5mg,产率35.7%)。4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6-methyl-1H-pyrrolo[2,3-b ] Pyridine as a raw material, referring to the fourth step of the example, 4-(2-(2,4-difluorophenoxy)-5-(1-(methylsulfonyl)ethyl)phenyl)-6 -Methyl-1H-pyrrolo[2,3-b]pyridine-7-oxide (18.5 mg, yield 35.7%).
1H NMR(400MHz,CDCl 3):δ12.38(s,1H),7.66(d,J=2.0Hz,1H),7.41-7.38(dd,J=8.4Hz,2.0Hz,1H),7.34-7.33(d,J=3.6Hz,1H),7.26(s,1H),7.03–6.91(m,2H),6.85-6.81(m,2H),6.58(d,J=3.2Hz,1H),4.27-4.21(q,J=7.2Hz,1H),2.78(s,3H),2.76(s,3H),1.83-1.81(d,J=7.2Hz,3H)。 1 H NMR (400MHz, CDCl 3 ): δ12.38 (s, 1H), 7.66 (d, J = 2.0Hz, 1H), 7.41-7.38 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.34- 7.33 (d, J = 3.6 Hz, 1H), 7.26 (s, 1H), 7.03 - 6.91 (m, 2H), 6.85 - 6.81 (m, 2H), 6.58 (d, J = 3.2 Hz, 1H), 4.27 - 4.21 (q, J = 7.2 Hz, 1H), 2.78 (s, 3H), 2.76 (s, 3H), 1.83-1.81 (d, J = 7.2 Hz, 3H).
MS m/z(ESI):459.1[M+H] + MS m/z (ESI): 459.1 [M+H] +
实施例102Example 102
6-环丙基-4-(2-(2,4-二氟苯氧基)-5-(乙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物6-Cyclopropyl-4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-7 -oxide
Figure PCTCN2018073989-appb-000285
Figure PCTCN2018073989-appb-000285
第一步:4-氯-6-环丙基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备First step: Preparation of 4-chloro-6-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000286
Figure PCTCN2018073989-appb-000286
将6-溴-4-氯-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(500mg,1.3mmol),环丙基硼酸(110mg,1.3mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(95mg,0.13mmol)和碳酸钾(537mg,3.9mmol)加入到二氧六环/水(v/v=4:1,20mL)混合溶剂中。反应液在氮气保护100℃下,反应10小时后将至室温,将反应液蒸干,柱分离(石油醚:乙酸乙酯=10:1)得到4-氯-6-环丙基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(170mg,产率38%)。6-Bromo-4-chloro-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (500 mg, 1.3 mmol), cyclopropylboronic acid (110 mg, 1.3 mmol), [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride (95 mg, 0.13 mmol) and potassium carbonate (537 mg, 3.9 mmol) were added to dioxane/water (v/v = 4:1, 20 mL) ) mixed solvent. The reaction solution was subjected to a nitrogen atmosphere at 100 ° C for 10 hours, and then allowed to reach room temperature. The reaction mixture was evaporated to dryness, and then purified (ethyl ether: ethyl acetate = 10:1) to give 4-chloro-6-cyclopropyl-1- Tosyl-1H-pyrrolo[2,3-b]pyridine (170 mg, yield 38%).
1H NMR(400MHz,CDCl 3):δ8.03(d,J=8.4Hz,2H),7.65(d,J=4.0Hz,1H),7.29(d,J=8.4Hz,2H),7.09(s,1H),6.59(d,J=4.0Hz,1H),2.40(s,3H),2.06–1.97(m,1H),1.14–1.06(m,2H),1.05–0.99(m,2H). 1 H NMR (400 MHz, CDCl 3 ): δ 8.03 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 4.0 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 7.09 ( s, 1H), 6.59 (d, J = 4.0 Hz, 1H), 2.40 (s, 3H), 2.06 - 1.97 (m, 1H), 1.14 - 1.06 (m, 2H), 1.05 - 0.99 (m, 2H) .
第二步:6-环丙基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶的制备Second step: 6-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H- Preparation of pyrrolo[2,3-b]pyridine
Figure PCTCN2018073989-appb-000287
Figure PCTCN2018073989-appb-000287
4-氯-6-环丙基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(170mg,0.49mmol),4,4,4',4',5,5,5',5'-八甲基-2,2'-联(1,3,2-二噁硼戊环)(373mg,1.47mmol),乙酸钾(144mg,1.47mmol),乙酸钯(5.5mg,24.6umol)和[1,1'-联苯基]-2-基二环己基磷烷(17.2mg,49umol)加入到二氧六环(10mL)中,反应液在氮气保护90℃下,反应10小时,反应液蒸干,柱分离(石油醚:乙酸乙酯=10:1)得到6-环丙基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(165mg,产率77%)。4-Chloro-6-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (170 mg, 0.49 mmol), 4,4,4',4',5,5,5 ',5'-octamethyl-2,2'-linked (1,3,2-dioxaborolan) (373 mg, 1.47 mmol), potassium acetate (144 mg, 1.47 mmol), palladium acetate (5.5 mg, 24.6 umol) and [1,1'-biphenyl]-2-yldicyclohexylphosphane (17.2 mg, 49 umol) were added to dioxane (10 mL), and the reaction was carried out under nitrogen at 90 ° C. After 10 hours, the reaction mixture was evaporated to dryness and purified (jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjs Dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridine (165 mg, yield 77%).
MS m/z(ESI):439.1[M+H] + MS m/z (ESI): 439.1 [M+H] +
第三步:N-(3-(6-环丙基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)-4-(2,4-二氟苯氧基)苯基)乙磺酰胺的制备The third step: N-(3-(6-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2,4-difluorobenzene Preparation of oxy)phenyl)ethanesulfonamide
Figure PCTCN2018073989-appb-000288
Figure PCTCN2018073989-appb-000288
将6-环丙基-4-(4,4,5,5-四甲基-1,3,2-二噁硼戊环-2-基)-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶(165mg,0.38mmol),N-(3-溴-4-(2,4-二氟苯氧基)苯基)乙磺酰胺 (177mg,0.45mmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(27.8mg,0.038mmol)和碳酸钾(130mg,0.94mmol)加入到二氧六环/水(v/v=4:1,10mL)混合溶剂中。反应液在氮气保护100℃下,反应10小时后冷却至室温,将反应液蒸干后用柱分离(石油醚:乙酸乙酯=10:3)得到N-(3-(6-环丙基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)-4-(2,4-二氟苯氧基)苯基)乙磺酰胺(100mg,产率43%)。6-Cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-toluenesulfonyl-1H-pyrrolo[ 2,3-b]pyridine (165 mg, 0.38 mmol), N-(3-bromo-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (177 mg, 0.45 mmol), [1, 1'-bis(diphenylphosphino)ferrocene]palladium dichloride (27.8 mg, 0.038 mmol) and potassium carbonate (130 mg, 0.94 mmol) were added to dioxane/water (v/v = 4: 1,10 mL) in a mixed solvent. The reaction solution was reacted at 100 ° C for 10 hours under nitrogen, and then cooled to room temperature. The reaction mixture was evaporated to dryness and then purified by column ( petroleum ether: ethyl acetate = 10:3) to give N-(3-(6-cyclopropyl) -1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide (100 mg, yield 43 %).
MS m/z(ESI):624.1[M+H] + MS m/z (ESI): 624.1 [M+H] +
第四步:N-(3-(6-环丙基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(2,4-二氟苯氧基)苯基)乙磺酰胺的制备Fourth step: N-(3-(6-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2,4-difluorophenoxy)phenyl) Preparation of ethanesulfonamide
Figure PCTCN2018073989-appb-000289
Figure PCTCN2018073989-appb-000289
将氢氧化钾(45mg,0.8mmol)加入到N-(3-(6-环丙基-1-甲苯磺酰-1H-吡咯并[2,3-b]吡啶-4-基)-4-(2,4-二氟苯氧基)苯基)乙磺酰胺(100mg,0.16mmol)的四氢呋喃(2mL)和水(3滴)溶液中,反应液在50℃下,反应12小时,LCMS显示反应没有进行,反应液冷却后加入乙醇(1mL),反应液在70℃下,反应5小时,反应液冷却后,加入二氯甲烷(15mL),用饱和食盐水(10mL×2)洗涤,用无水硫酸钠干燥后过滤,将滤液浓缩得到粗品N-(3-(6-环丙基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(2,4-二氟苯氧基)苯基)乙磺酰胺(78mg),粗品直接用于下一步。Potassium hydroxide (45 mg, 0.8 mmol) was added to N-(3-(6-cyclopropyl-1-toluenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4- (2,4-Difluorophenoxy)phenyl)ethanesulfonamide (100 mg, 0.16 mmol) in tetrahydrofuran (2 mL) and water (3 drops), the reaction mixture was reacted at 50 ° C for 12 hours, LCMS showed The reaction was not carried out. After the reaction solution was cooled, ethanol (1 mL) was added, and the reaction mixture was reacted at 70 ° C for 5 hours. After the reaction solution was cooled, dichloromethane (15 mL) was added and washed with saturated brine (10 mL×2). After drying over anhydrous sodium sulfate and filtering, the filtrate was concentrated to give crude N-(3-(6-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2,4- Difluorophenoxy)phenyl)ethanesulfonamide (78 mg) was used directly in the next step.
MS m/z(ESI):470.1[M+H] + MS m/z (ESI): 470.1 [M+H] +
第五步:6-环丙基-4-(2-(2,4-二氟苯氧基)-5-(乙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物的制备Step 5: 6-Cyclopropyl-4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-1H-pyrrolo[2,3-b Preparation of pyridine-7-oxide
Figure PCTCN2018073989-appb-000290
Figure PCTCN2018073989-appb-000290
将间氯过氧苯甲酸(29mg,0.12mmol,75%)加入到N-(3-(6-环丙基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(2,4-二氟苯氧基)苯基)乙磺酰胺(39mg,0.083mmol)的四氢呋喃(1mL)溶液中。室温反应10分钟后用饱和硫代硫酸钠(10mL)淬灭,二氯甲烷萃取(10mL×2),有机相合并后用饱和碳酸氢钠(10mL×2)洗涤,用无水硫酸钠干燥,过滤后将滤液蒸干得到粗品,粗品经制备板分离(二氯甲烷:甲醇=20:1)得到6-环丙基-4-(2-(2,4-二氟苯氧基)-5-(乙基磺酰氨基)苯基)-1H-吡咯并[2,3-b]吡啶-7-氧化物(5mg,产率12%)。m-Chloroperoxybenzoic acid (29 mg, 0.12 mmol, 75%) was added to N-(3-(6-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-4- (2,4-Difluorophenoxy)phenyl)ethanesulfonamide (39 mg, 0.083 mmol) in tetrahydrofuran (1 mL). After reacting for 10 minutes at room temperature, it was diluted with EtOAc EtOAc (EtOAc m. After filtration, the filtrate was evaporated to dryness to give a crude material, which was purified (yield: methylene chloride:methanol = 20:1) to give 6-cyclopropyl-4-(2-(2,4-difluorophenoxy)-5 -(Ethylsulfonylamino)phenyl)-1H-pyrrolo[2,3-b]pyridine-7-oxide (5 mg, yield 12%).
1H NMR(400MHz,CDCl 3):δ11.90(br,1H),9.13(br,1H),7.44–7.32(m,2H), 7.25(s,1H),6.91–6.79(m,3H),6.78–6.68(m,2H),6.48(s,1H),3.29–3.13(m,2H),2.90–2.72(m,1H),1.42(t,J=7.1Hz,3H),1.10–0.94(m,2H),0.78–0.64(m,2H). 1 H NMR (400MHz, CDCl 3 ): δ11.90 (br, 1H), 9.13 (br, 1H), 7.44-7.32 (m, 2H), 7.25 (s, 1H), 6.91-6.79 (m, 3H) , 6.78–6.68 (m, 2H), 6.48 (s, 1H), 3.29–3.13 (m, 2H), 2.90–2.72 (m, 1H), 1.42 (t, J = 7.1 Hz, 3H), 1.10–0.94 (m, 2H), 0.78–0.64 (m, 2H).
MS m/z(ESI):486.1[M+H] + MS m/z (ESI): 486.1 [M+H] +
实施例103Example 103
化合物103至化合物609的合成工艺基本参照实施例26的实验步骤。The synthesis process of Compound 103 to Compound 609 is basically referred to the experimental procedure of Example 26.
生物学评价Biological evaluation
以下测试例用于进一步解释本发明,但这些测试例并非意味着限制本发明的范围。The following test examples are intended to further illustrate the invention, but these test examples are not intended to limit the scope of the invention.
测试例1、测定本发明化合物对BRD4结合活性的抑制作用Test Example 1. Determination of the inhibitory effect of the compound of the present invention on BRD4 binding activity
BRD4结合活性测试通过以下的方法进行测试。The BRD4 binding activity test was tested by the following method.
实验步骤Experimental procedure
为了测试化合物对BRD4与乙酰化蛋白结合活性的影响,本实验采用荧光共振能量转移(TR-FRET)的方法,测试化合物对BRD4与乙酰化底物结合活性的抑制作用,并得出化合物对BRD4结合活性的半数抑制浓度IC 50In order to test the effect of compounds on the binding activity of BRD4 to acetylated protein, this experiment used fluorescence resonance energy transfer (TR-FRET) method to test the inhibitory effect of compounds on the binding activity of BRD4 to acetylated substrate, and obtained the compound against BRD4. binding activity half maximal inhibitory concentration IC 50.
具体实验操作如下:The specific experimental operation is as follows:
1、在384孔板中加入1~5ul BRD4酶溶液,酶终浓度为1~20nM;1. Add 1 to 5 ul of BRD4 enzyme solution to the 384-well plate, and the final concentration of the enzyme is 1 to 20 nM;
2、加入1~5ul梯度稀释好的化合物溶液;2. Add 1 to 5 ul of the gradient diluted compound solution;
3、加入1~5ul底物混合液包含乙酰化底物多肽终浓度2~50nM;3, adding 1 ~ 5ul substrate mixture containing acetylated substrate polypeptide final concentration of 2 ~ 50nM;
4、室温孵育0.5~3小时;4. Incubate for 0.5 to 3 hours at room temperature;
5、加入10ul EDTA和含标记抗体的检测液,室温孵育1小时;5. Add 10 ul of EDTA and the labeled antibody-containing test solution, incubate for 1 hour at room temperature;
6、酶标仪测定各板孔的665nm荧光信号值;6. The 665 nm fluorescence signal value of each plate hole was measured by a microplate reader;
7、通过荧光信号值计算抑制率;7. Calculate the inhibition rate by the fluorescence signal value;
8、根据不同浓度的抑制率通过曲线拟合得出化合物的IC 508. A compound according to obtain IC 50 inhibition rate of different concentration by curve fitting.
本发明化合物对BRD4结合活性的抑制作用,通过以上的试验进行测定,测得的IC 50值见表1。 The inhibitory effect of the compound of the present invention on the binding activity of BRD4 was measured by the above test, and the IC 50 values measured are shown in Table 1.
表1本发明化合物对BRD4结合活性抑制IC 50Table 1 IC 50 values of the compounds of the invention against BRD4 binding activity
实施例编号Example number IC 50(nM) IC 50 (nM) 实施例编号Example number IC 50(nM) IC 50 (nM)
11 7.37.3 5151 5.15.1
22 24.124.1 5252 16.316.3
44 29.129.1 5353 14.414.4
55 15.915.9 5454 19.319.3
66 19.619.6 5555 40.540.5
77 23.123.1 5656 17.517.5
88 6.06.0 5959 18.418.4
99 12.412.4 6060 9.99.9
1010 14.414.4 6161 17.317.3
1212 31.231.2 6262 17.817.8
1313 9.39.3 6363 21.121.1
1414 26.326.3 6767 26.426.4
1515 28.828.8 6868 20.720.7
1616 13.013.0 6969 19.019.0
1717 9.19.1 7171 9.89.8
1919 32.332.3 7272 14.814.8
21twenty one 29.929.9 7373 14.114.1
22twenty two 34.334.3 7474 16.916.9
23twenty three 11.511.5 7575 11.611.6
2626 6.76.7 7676 6.16.1
2727 15.915.9 7777 12.612.6
2828 12.212.2 7878 23.023.0
3030 30.530.5 7979 25.125.1
3131 15.415.4 8080 22.022.0
3232 15.915.9 8181 21.521.5
3333 3.93.9 8282 16.516.5
3434 4.54.5 8383 21.821.8
3535 4.24.2 8484 9.99.9
3636 8.98.9 8585 35.535.5
3737 20.120.1 8686 10.810.8
3838 32.332.3 8787 26.926.9
3939 34.134.1 8989 18.918.9
4040 38.238.2 9090 13.813.8
4141 27.327.3 9191 3.23.2
4242 44.544.5 9292 2.42.4
4343 31.931.9 9393 22.322.3
4444 18.418.4 9595 19.619.6
4545 46.246.2 9696 45.045.0
4646 5.75.7 9797 8.08.0
4747 21.921.9 9898 8.78.7
4848 27.427.4 9999 27.527.5
4949 30.230.2 100100 11.911.9
5050 23.423.4 101101 16.416.4
结论:本发明化合物对BRD4结合活性具有明显的抑制作用。Conclusion: The compounds of the present invention have a significant inhibitory effect on BRD4 binding activity.
测试例2、测定本发明化合物对结肠癌肿瘤细胞colo205增殖活性的抑制作用Test Example 2, Determination of the inhibitory effect of the compound of the present invention on the proliferation activity of colon cancer tumor cell colo205
化合物对结肠癌肿瘤细胞colo205增殖活性通过以下的方法进行测试。The compound's proliferative activity against colon cancer tumor cell colo205 was tested by the following method.
实验步骤Experimental procedure
本实验采用CellTiter-Glo的方法测试化合物对colo205细胞增殖活性的抑制作用,并得出化合物抑制细胞增殖活性的半数抑制浓度IC 50Inhibitory activity of the present study, the method of CellTiter-Glo colo205 test compound on the proliferation of cells, inhibit cell proliferation and the compound obtained half maximal inhibitory concentration IC 50 activity.
1、在96孔细胞培养板中接种50~100μL的colo205细胞悬液,密度为1~5×10 4细胞/mL,将培养板于培养箱培养16~24小时(37℃,5%CO 2)。 1. Inoculate 50-100 μL of colo205 cell suspension in a 96-well cell culture plate at a density of 1 to 5×10 4 cells/mL. Incubate the plate in an incubator for 16 to 24 hours (37 ° C, 5% CO 2 ). ).
2、向培养板细胞中加入梯度稀释的不同浓度的待测化合物溶液,将培养板在培养箱孵育6天(37℃,5%CO 2)。 2. Add gradient dilutions of different concentrations of the test compound solution to the culture plate cells, and incubate the culture plates in the incubator for 6 days (37 ° C, 5% CO 2 ).
3、每孔加入50~100μL CellTiter-Glo试剂,并振荡10分钟,室温静置10分钟。3. Add 50-100 μL of CellTiter-Glo reagent to each well, shake for 10 minutes, and let stand for 10 minutes at room temperature.
4、酶标仪测定各板的化学发光信号值。4. The plate reader measures the chemiluminescence signal value of each plate.
5、通过化学发光信号值计算抑制率。5. Calculate the inhibition rate by the value of the chemiluminescence signal.
6、根据不同浓度的抑制率通过曲线拟合得出化合物的IC 506, obtained according to compound IC 50 inhibition rate of different concentration by curve fitting.
本发明化合物对结肠癌肿瘤细胞colo205增殖活性进行测定,测得的IC 50值见表2。 The compound of the present invention was assayed for the proliferative activity of colon cancer tumor cell colo205, and the measured IC 50 values are shown in Table 2.
表2本发明化合物对结肠癌肿瘤细胞colo205增殖活性抑制IC 50Table 2 IC 50 values of the compounds of the present invention inhibiting the proliferation activity of colon cancer tumor cell colo205
实施例编号Example number IC 50(nM) IC 50 (nM)
11 3636
1010 42.242.2
2626 6.76.7
2727 66.666.6
2828 65.265.2
3131 67.367.3
3232 80.280.2
3333 55.455.4
3535 53.753.7
3737 76.676.6
4444 46.246.2
6060 31.631.6
9797 46.746.7
9898 3.43.4
结论:本发明化合物对结肠癌肿瘤细胞colo205增殖活性具有明显的抑制作用。Conclusion: The compound of the present invention has a significant inhibitory effect on the proliferation activity of colon cancer tumor cell colo205.
测试例3、测定本发明化合物对白血病细胞MV4-11增殖活性的抑制作用Test Example 3, Determination of the inhibitory effect of the compound of the present invention on the proliferative activity of leukemia cell MV4-11
化合物对白血病细胞MV4-11增殖活性的抑制作用通过以下的方法进行测试。The inhibitory effect of the compound on the proliferative activity of leukemia cell MV4-11 was tested by the following method.
本实验采用CellTiter-Glo的方法测试化合物对MV4-11细胞增殖的抑制作用,并得出化合物抑制细胞增殖活性的半数抑制浓度IC 50This experiment uses the CellTiter-Glo method for testing compounds for inhibition of the proliferation of MV4-11 cells, the compounds inhibit cell proliferation and draw half maximal inhibitory concentration IC 50 activity.
实验步骤:Experimental steps:
1、在96孔细胞培养板中接种50~100μL的MV4-11细胞悬液,密度为1~5×10 4细胞/mL,将培养板于培养箱培养16~24小时(37℃,5%CO 2)。 1. Inoculate 50-100 μL of MV4-11 cell suspension in a 96-well cell culture plate at a density of 1 to 5×10 4 cells/mL. Incubate the plate in an incubator for 16 to 24 hours (37 ° C, 5%). CO 2 ).
2、向培养板细胞中加入梯度稀释的不同浓度的待测化合物溶液,将培养板在培养箱孵育72小时(37℃,5%CO 2)。 2. Add gradient dilutions of different concentrations of the test compound solution to the culture plate cells, and incubate the plate for 72 hours (37 ° C, 5% CO 2 ) in the incubator.
3、每孔加入50~100μL CellTiter-Glo试剂,并振荡10分钟,室温静置10分钟。3. Add 50-100 μL of CellTiter-Glo reagent to each well, shake for 10 minutes, and let stand for 10 minutes at room temperature.
4、酶标仪测定各板的化学发光信号值。4. The plate reader measures the chemiluminescence signal value of each plate.
5、通过化学发光信号值计算抑制率。5. Calculate the inhibition rate by the value of the chemiluminescence signal.
6、根据不同浓度的抑制率通过曲线拟合得出化合物的IC 506, obtained according to compound IC 50 inhibition rate of different concentration by curve fitting.
本发明化合物对白血病细胞MV4-11增殖活性进行测定,测得的IC 50值见表3。 The compound of the present invention was assayed for the proliferative activity of leukemia cell MV4-11, and the measured IC 50 values are shown in Table 3.
表3本发明化合物对白血病细胞MV4-11增殖活性抑制IC 50Table 3 IC 50 values of the compounds of the present invention inhibiting the proliferation of leukemia cell MV4-11
实施例编号Example number IC 50(nM) IC 50 (nM) 实施例编号Example number IC 50(nM) IC 50 (nM)
11 3.93.9 5252 1.71.7
22 6.06.0 5353 0.200.20
44 6.06.0 5454 1.61.6
55 2.92.9 5555 2.52.5
66 1.41.4 5656 4.04.0
77 9.59.5 5959 9.29.2
88 0.700.70 6060 6.56.5
99 1.51.5 6161 9.79.7
1010 3.33.3 6262 6.36.3
1212 11.111.1 6363 6.56.5
1313 1.41.4 6464 12.812.8
1414 2.12.1 6565 21.921.9
1515 1.91.9 6666 9.29.2
1616 4.64.6 6767 1.41.4
1717 3.93.9 6868 2.22.2
1818 16.616.6 6969 2.72.7
1919 24.624.6 7171 2.22.2
2020 14.914.9 7272 1.61.6
21twenty one 26.226.2 7373 1.61.6
23twenty three 3.63.6 7474 2.12.1
2525 46.946.9 7575 1.11.1
2626 1.41.4 7676 0.80.8
2727 2.72.7 7777 0.30.3
2828 4.34.3 7878 4.64.6
2929 12.112.1 7979 14.114.1
3030 14.814.8 8080 2.12.1
3131 5.35.3 8181 4.64.6
3232 10.610.6 8282 5.45.4
3333 3.23.2 8383 2.02.0
3434 11.211.2 8484 1.51.5
3535 1.81.8 8585 10.310.3
3636 7.17.1 8686 2.02.0
3737 5.25.2 8787 13.413.4
3838 8.28.2 8888 40.940.9
3939 6.46.4 8989 4.04.0
4040 40.240.2 9090 4.04.0
4141 4.74.7 9191 0.50.5
4242 17.217.2 9292 1.11.1
4343 3.23.2 9393 7.97.9
4444 2.22.2 9494 28.028.0
4545 34.934.9 9595 2.32.3
4646 4.74.7 9696 39.039.0
4747 12.012.0 9797 7.37.3
4848 21.021.0 9898 1.81.8
4949 3.03.0 9999 11.611.6
5050 5.15.1 100100 1.71.7
5151 0.80.8 101101 2.52.5
    102102 48.048.0
测试例4、本发明化合物对小鼠的PK分析测试Test Example 4, PK analysis test of the compound of the present invention on mice
本发明优选实施例的小鼠药物代谢动力学试验,采用Balb/c小鼠(上海杰思捷实验动物有限公司)进行。The mouse pharmacokinetic test of the preferred embodiment of the present invention was carried out using Balb/c mice (Shanghai Jiesijie Experimental Animal Co., Ltd.).
给药方式:单次灌胃给药Mode of administration: single intragastric administration
给药剂量:5毫克/10毫升/千克Dosage: 5 mg / 10 ml / kg
制剂处方:0.5%CMC-Na和1%Tween 80,超声溶解Formulation formulation: 0.5% CMC-Na and 1% Tween 80, sonicated
取样点:给药后0.5、1、2、4、6、8和24小时Sampling point: 0.5, 1, 2, 4, 6, 8 and 24 hours after administration
样品处理:Sample processing:
静脉采血0.1mL,置于K 2EDTA试管中,室温1000~3000×g离心5~20min分离血浆,于-80℃保存。 0.1 mL of venous blood was collected and placed in a K 2 EDTA test tube, and the plasma was separated by centrifugation at 1000 to 3000 × g for 5 to 20 minutes at room temperature, and stored at -80 ° C.
血浆样品40uL加入160uL乙腈沉淀,混合后500~2000×g离心5~20分钟。The plasma sample was added to 160 uL of acetonitrile precipitate, and after mixing, it was centrifuged at 500 to 2000 × g for 5 to 20 minutes.
取处理后的上清溶液100uL,采用LC/MS/MS分析待测化合物的浓度,LC/MS/MS分析仪器:AB Sciex API 4000。The treated supernatant solution was taken for 100 uL, and the concentration of the test compound was analyzed by LC/MS/MS. LC/MS/MS analytical instrument: AB Sciex API 4000.
液相条件:Shimadzu LC-20AD泵Liquid phase conditions: Shimadzu LC-20AD pump
色谱柱:phenomenex Gemiu 5μm C18 50×4.6mmColumn: phenomenex Gemiu 5μm C18 50×4.6mm
移动相:A液为0.1%甲酸水溶液,B液为乙腈Mobile phase: solution A is 0.1% aqueous formic acid, and solution B is acetonitrile.
流速:0.8mL/minFlow rate: 0.8mL/min
药代动力学:Pharmacokinetics:
主要参数用WinNonlin 6.1计算得到,小鼠药代实验结果见下表4The main parameters were calculated using WinNonlin 6.1, and the results of the mouse pharmacokinetic experiments are shown in Table 4 below.
Figure PCTCN2018073989-appb-000291
Figure PCTCN2018073989-appb-000291
从表中小鼠药代实验结果可以看出:本发明实施例化合物表现出良好的代谢性质,暴露量AUC和最大血药浓度Cmax都表现良好。It can be seen from the results of the mouse pharmacokinetic experiments in the table that the compounds of the examples of the present invention exhibited good metabolic properties, and both the exposure AUC and the maximum blood concentration Cmax performed well.

Claims (17)

  1. 一种通式(I)所示的化合物:A compound of the formula (I):
    Figure PCTCN2018073989-appb-100001
    Figure PCTCN2018073989-appb-100001
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用的盐,Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中:among them:
    X、Y各自独立地选自键、N、O、-NR 5-、-(CR 6R 7) x-和-(CR 6R 7) xN(R 5) y-; X, Y are each independently selected from the group consisting of a bond, N, O, -NR 5 -, -(CR 6 R 7 ) x -, and -(CR 6 R 7 ) x N(R 5 ) y -;
    Z选自-NR 5-、O和-O(CR 6R 7) x-; Z is selected from -NR 5 -, O and -O(CR 6 R 7 ) x -;
    环A选自环烷基、杂环基、芳基和杂芳基;Ring A is selected from the group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
    R 1选自烷基、环烷基和烯基;其中所述的烷基、烯基和环烷基任选进一步被选自烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、环烷基、杂环基、芳基和杂芳基的中的一个或多个取代基所取代; R 1 is selected from the group consisting of alkyl, cycloalkyl and alkenyl; wherein said alkyl, alkenyl and cycloalkyl are optionally further selected from the group consisting of alkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy Substituted by one or more substituents of a group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
    R 2选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、烯烃、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10;其中所述的烷基、卤代烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, an olefin, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C( O) R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected from alkyl, haloalkanes Base, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O) R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S (O) substituted with one or more substituents in m R 10 ;
    R 3选自不存在、氢原子、烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10;其中所述的烷基、卤代烷基、烯烃、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤代烷基、卤素、氨基、硝基、氰基、羟基、烷氧基、卤代烷氧基、羟烷基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; R 3 is selected from the group consisting of a non-existent hydrogen atom, an alkyl group, a halogenated alkyl group, an alkene group, an alkoxy group, a halogenated alkoxy group, a halogen group, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, and a hetero group. Aryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl, haloalkyl, olefin, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further selected From alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 And one or more substituents in -NR 9 S(O) m R 10 are substituted;
    或者,R 2和R 3连接形成一个杂环基或杂芳基;其中所述的杂环基和杂芳基 任选进一步被选自烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; Alternatively, R 2 and R 3 are bonded to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl are optionally further selected from the group consisting of alkyl, haloalkyl, alkene, alkoxy, haloalkoxy , halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S (O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m One or more substitutions in R 10 Substituted by
    再或者,R 2、R 3各自独立地与X基团上的R 6、R 7或R 5连接形成一个杂环基或杂芳基;其中所述的杂环基和杂芳基任选进一步被选自烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; Further, R 2 and R 3 are each independently bonded to R 6 , R 7 or R 5 on the X group to form a heterocyclic or heteroaryl group; wherein said heterocyclic group and heteroaryl group are optionally further Selected from alkyl, haloalkyl, olefin, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 And one or more substituents in -NR 9 S(O) m R 10 are substituted;
    R 4独立地选自氢原子、烷基、卤代烷基、烷氧基、卤代烷氧基、羟烷基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-(CH 2) tNR 9R 10、-(CH 2) tC(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10;其中所述的烷基、环烷基、杂环基、芳基、杂芳基任选进一步被选自烷基、卤代烷基、烯烃、烷氧基、卤代烷氧基、羟烷基、卤素、卤代烷基、烷基取代杂环基、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; R 4 is independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group, an aryl group, Heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -(CH 2 ) t NR 9 R 10 , -(CH 2 ) t C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ; wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Further optionally, it is selected from the group consisting of alkyl, haloalkyl, olefin, alkoxy, haloalkoxy, hydroxyalkyl, halogen, haloalkyl, alkyl substituted heterocyclic, amino, nitro, hydroxy, cyano, cyclo Alkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 ,- Substituting one or more substituents of C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ;
    R 5选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基; R 5 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
    R 6和R 7各自独立地选自氢原子、烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group, a hydroxyalkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a nitro group, a hydroxyl group, a cyano group, a cycloalkyl group, a heterocyclic group. , aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ;
    或者,R 6和R 7可以形成环烷基或杂环基,该环烷基或杂环基任选进一步被选自烷基、卤代烷基、羟烷基、烷氧基、卤代烷氧基、卤素、氨基、硝基、羟基、氰基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; Alternatively, R 6 and R 7 may form a cycloalkyl or heterocyclic group, which is optionally further selected from the group consisting of alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, halogen , amino, nitro, hydroxy, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O m R 8 , -NR 9 R 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m One or more substituents in R 10 Replace
    R 8选自氢原子、烷基、卤代烷基、烯基、羟基、氨基、烷氧基、卤代烷氧基、环烷基、杂环基、芳基和杂芳基;其中所述的烷基、卤代烷基、烯基、环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、卤代烷基、氨基、硝基、氰基、羟基、羟烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、-OR 8、-C(O)R 8、-C(O)OR 8、-S(O) mR 8、-NR 9R 10、-C(O)NR 9R 10、-NR 9C(O)R 10和-NR 9S(O) mR 10中的一个或多个取代基所取代; R 8 is selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkenyl group, a hydroxyl group, an amino group, an alkoxy group, a halogenated alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein the alkyl group, Haloalkyl, alkenyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halo, haloalkyl, amino, nitro, cyano, hydroxy, hydroxyalkyl, alkoxy Base, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 8 , -C(O)R 8 , -C(O)OR 8 , -S(O) m R 8 , -NR 9 R Substituting one or more substituents of 10 , -C(O)NR 9 R 10 , -NR 9 C(O)R 10 and -NR 9 S(O) m R 10 ;
    R 9和R 10相同或不同,且各自独立地选自氢原子、烷基、羟基、氨基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基和杂芳 基任选进一步被选自烷基、卤素、羟基、氨基、硝基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代; R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a hydroxyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group And a heterocyclic group, an aryl group and a heteroaryl group are further selected from the group consisting of an alkyl group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group. And substituted with one or more substituents in the heteroaryl;
    m为0、1或2的整数;m is an integer of 0, 1, or 2;
    n为0、1、2、3、4或5的整数;n is an integer of 0, 1, 2, 3, 4 or 5;
    t为0、1、2、3、4或5的整数;t is an integer of 0, 1, 2, 3, 4 or 5;
    x为0、1、2、3或4的整数;且x is an integer of 0, 1, 2, 3 or 4;
    y为0或1的整数。y is an integer of 0 or 1.
  2. 根据权利要求1所述的化合物,其为通式(II)所示的化合物:A compound according to claim 1 which is a compound of the formula (II):
    Figure PCTCN2018073989-appb-100002
    Figure PCTCN2018073989-appb-100002
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中:among them:
    B选自CH和N;B is selected from CH and N;
    R 1~R 4、Z、X、Y和n如权利要求1中所定义。 R 1 to R 4 , Z, X, Y and n are as defined in claim 1.
  3. 根据权利要求1所述的化合物,其为通式(III)所示的化合物:A compound according to claim 1 which is a compound of the formula (III):
    Figure PCTCN2018073989-appb-100003
    Figure PCTCN2018073989-appb-100003
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中:among them:
    B选自CH和N;B is selected from CH and N;
    R 1、R 2、R 4、Z、X和n如权利要求1中所定义。 R 1 , R 2 , R 4 , Z, X and n are as defined in claim 1.
  4. 通式(IV)所示的化合物:a compound of the formula (IV):
    Figure PCTCN2018073989-appb-100004
    Figure PCTCN2018073989-appb-100004
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中:among them:
    Z选自NH和O;Z is selected from NH and O;
    B选自CH和N;B is selected from CH and N;
    环C选自环烷基、杂环基、芳基和杂芳基,其中所述的环烷基、杂环基、芳基和杂芳基任选进一步被选自烷基、卤素、氨基、硝基、羟基、氰基、烷氧基、羟烷基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;且Ring C is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally further selected from the group consisting of alkyl, halogen, amino, Substituted by one or more substituents of a nitro group, a hydroxyl group, a cyano group, an alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;
    z为0、1、2或3的整数;z is an integer of 0, 1, 2 or 3;
    R 1、R 2、R 4、X和n如权利要求1中所定义。 R 1 , R 2 , R 4 , X and n are as defined in claim 1.
  5. 根据权利要求4所述的化合物,其为通式(VA)或(VB)所示的化合物:The compound according to claim 4 which is a compound represented by the formula (VA) or (VB):
    Figure PCTCN2018073989-appb-100005
    Figure PCTCN2018073989-appb-100005
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中:among them:
    Z选自NH和O;Z is selected from NH and O;
    X选自键、NH和-CR 6R 7-; X is selected from the group consisting of a bond, NH and -CR 6 R 7 -;
    R 4独立地选自氢原子、卤素、羟基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6羟烷基、C 3-6环烷基、-(CH 2) tNR 9R 10和-(CH 2) tC(O)NR 9R 10R 4 is independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 3-6 cycloalkyl group, -( CH 2 ) t NR 9 R 10 and -(CH 2 ) t C(O)NR 9 R 10 ;
    R 2选自C 1-6烷基、卤代C 1-6烷基、-NR 9R 10、C 3-6环烷基和5-6元杂芳基;其中所述的C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基和5-6元杂芳基任选进一步被选自C 1-6烷基、卤代C 1-6烷基、卤素、氨基、氰基和羟基中的一个或多个取代基所取代; R 2 is selected from C 1-6 alkyl, halo C 1-6 alkyl, -NR 9 R 10 , C 3-6 cycloalkyl and 5-6 membered heteroaryl; wherein said C 1-6 The alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are further optionally selected from C 1-6 alkyl groups, halogenated C 1-6 alkyl groups, halogen Substituting one or more substituents of an amino group, a cyano group and a hydroxyl group;
    R 6、R 7相同或不同,各自独立地选自氢原子和C 1-3烷基; R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group;
    R 9、R 10相同或不同,各自独立地选自氢原子和C 1-3烷基; R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group;
    n、t如权利要求1中所定义。n, t as defined in claim 1.
  6. 根据权利要求4所述的化合物,其为通式(VIA)或(VIB)所示的化合物:A compound according to claim 4 which is a compound of the formula (VIA) or (VIB):
    Figure PCTCN2018073989-appb-100006
    Figure PCTCN2018073989-appb-100006
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中:among them:
    Z选自NH和O;Z is selected from NH and O;
    X选自键、NH和-CR 6R 7-; X is selected from the group consisting of a bond, NH and -CR 6 R 7 -;
    R 4独立地选自氢原子、卤素、羟基、氰基、C 1-6烷基、卤代C 1-6烷基、C 1-6羟烷基、C 3-6环烷基、-(CH 2) tNR 9R 10和-(CH 2) tC(O)NR 9R 10R 4 is independently selected from the group consisting of a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a C 1-6 alkyl group, a halogenated C 1-6 alkyl group, a C 1-6 hydroxyalkyl group, a C 3-6 cycloalkyl group, -( CH 2 ) t NR 9 R 10 and -(CH 2 ) t C(O)NR 9 R 10 ;
    R 2选自C 1-6烷基、卤代C 1-6烷基、-NR 9R 10、C 3-6环烷基和5-6元杂芳基;其中所述的C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基和5-6元杂芳基任选进一步被选自C 1-6烷基、卤代C 1-6烷基、卤素、氨基、氰基和羟基中的一个或多个取代基所取代; R 2 is selected from C 1-6 alkyl, halo C 1-6 alkyl, -NR 9 R 10 , C 3-6 cycloalkyl and 5-6 membered heteroaryl; wherein said C 1-6 The alkyl group, halo C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are further optionally selected from C 1-6 alkyl groups, halogenated C 1-6 alkyl groups, halogen Substituting one or more substituents of an amino group, a cyano group and a hydroxyl group;
    R 6、R 7相同或不同,各自独立地选自氢原子和C 1-3烷基; R 6 and R 7 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group;
    R 9、R 10相同或不同,各自独立地选自氢原子和C 1-3烷基; R 9 and R 10 are the same or different and are each independently selected from a hydrogen atom and a C 1-3 alkyl group;
    t如权利要求1中所定义。t as defined in claim 1.
  7. 根据权利要求1-4中任一项所述的化合物,其中R 1选自C 1-8烷基、C 2-8烯基和C 3-8环烷基;优选C 1-6烷基、C 2-6烯基或C 3-6环烷基;更优选C 1-3烷基、C 2-3烯基或C 3-6环烷基;最优选甲基。 The compound according to any one of claims 1 to 4, wherein R 1 is selected from the group consisting of C 1-8 alkyl, C 2-8 alkenyl and C 3-8 cycloalkyl; preferably C 1-6 alkyl, C 2-6 alkenyl or C 3-6 cycloalkyl; more preferably C 1-3 alkyl, C 2-3 alkenyl or C 3-6 cycloalkyl; most preferred is methyl.
  8. 根据权利要求1-6中任一项所述的化合物,其中R 2选自C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基和5-6元杂芳基,其中所述的C 1-6烷基、卤代C 1-6烷基、C 3-6环烷基和5-6元杂芳基任选进一步被选自C 1-6烷基、卤代C 1-6烷基、卤素、氨基、氰基和羟基中的一个或多个取代基所取代;优选C 1-6烷基、卤代C 1-6烷基或C 3-6环烷基;更优选C 1-3烷基、卤代C 1-3烷基或C 3-6环烷基,最优选甲基、乙 基、异丙基、环丙基、环丁基、
    Figure PCTCN2018073989-appb-100007
    The compound according to any one of claims 1 to 6, wherein R 2 is selected from the group consisting of C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl and 5-6 membered heteroaryl a group wherein the C 1-6 alkyl group, halogenated C 1-6 alkyl group, C 3-6 cycloalkyl group and 5-6 membered heteroaryl group are further selected from a C 1-6 alkyl group, Substituted by one or more substituents of a halogenated C 1-6 alkyl, halogen, amino, cyano and hydroxy; preferably C 1-6 alkyl, halo C 1-6 alkyl or C 3-6 ring Alkyl; more preferably C 1-3 alkyl, halo C 1-3 alkyl or C 3-6 cycloalkyl, most preferably methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl,
    Figure PCTCN2018073989-appb-100007
  9. 根据权利要求1-8任一项所述的化合物,其特征在于,选自如下化合物:The compound according to any one of claims 1-8, which is selected from the group consisting of:
    Figure PCTCN2018073989-appb-100008
    Figure PCTCN2018073989-appb-100008
    Figure PCTCN2018073989-appb-100009
    Figure PCTCN2018073989-appb-100009
    Figure PCTCN2018073989-appb-100010
    Figure PCTCN2018073989-appb-100010
    Figure PCTCN2018073989-appb-100011
    Figure PCTCN2018073989-appb-100011
    Figure PCTCN2018073989-appb-100012
    Figure PCTCN2018073989-appb-100012
    Figure PCTCN2018073989-appb-100013
    Figure PCTCN2018073989-appb-100013
    Figure PCTCN2018073989-appb-100014
    Figure PCTCN2018073989-appb-100014
    Figure PCTCN2018073989-appb-100015
    Figure PCTCN2018073989-appb-100015
    Figure PCTCN2018073989-appb-100016
    Figure PCTCN2018073989-appb-100016
    Figure PCTCN2018073989-appb-100017
    Figure PCTCN2018073989-appb-100017
    Figure PCTCN2018073989-appb-100018
    Figure PCTCN2018073989-appb-100018
    Figure PCTCN2018073989-appb-100019
    Figure PCTCN2018073989-appb-100019
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用的盐。Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
  10. 权利要求1-9任一所述的化合物的中间体,其为通式(V)化合物、通式(VAA)化合物或通式(VBB)化合物:An intermediate of the compound according to any one of claims 1-9, which is a compound of the formula (V), a compound of the formula (VAA) or a compound of the formula (VBB):
    Figure PCTCN2018073989-appb-100020
    Figure PCTCN2018073989-appb-100020
    或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式,或其可药用盐,Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,
    其中:among them:
    R 1~R 4、环A、Z、X、Y和n如权利要求1中所定义。 R 1 ~ R 4, ring A, Z, X, Y and n are as defined in claim 1.
  11. 权利要求1-9任一项所述的化合物的制备方法,包括如下步骤:A method of preparing a compound according to any one of claims 1-9, comprising the steps of:
    Figure PCTCN2018073989-appb-100021
    Figure PCTCN2018073989-appb-100021
    通式(V)化合物经氧化剂氧化后得到通式(I)化合物;氧化剂优选间氯过氧苯甲酸;The compound of the formula (V) is oxidized by an oxidizing agent to give a compound of the formula (I); the oxidizing agent is preferably m-chloroperoxybenzoic acid;
    其中:among them:
    R 1~R 4、环A、Z、X、Y和n如权利要求1中所定义。 R 1 to R 4 , ring A, Z, X, Y and n are as defined in claim 1.
  12. 根据权利要求5所述的化合物的制备方法,包括如下步骤:The method of preparing a compound according to claim 5, comprising the steps of:
    Figure PCTCN2018073989-appb-100022
    Figure PCTCN2018073989-appb-100022
    通式(VAA)化合物经氧化剂氧化后得到通式(VA)化合物;氧化剂优选间氯过氧苯甲酸;The compound of the formula (VAA) is oxidized by an oxidizing agent to give a compound of the formula (VA); the oxidizing agent is preferably m-chloroperoxybenzoic acid;
    其中:among them:
    R 2、R 4、Z、X和n如权利要求5中所定义。 R 2 , R 4 , Z, X and n are as defined in claim 5.
  13. 根据权利要求5所述的化合物的制备方法,包括如下步骤:The method of preparing a compound according to claim 5, comprising the steps of:
    Figure PCTCN2018073989-appb-100023
    Figure PCTCN2018073989-appb-100023
    通式(VBB)化合物经氧化剂氧化后得到通式(VB)化合物;氧化剂优选间氯过氧苯甲酸;The compound of the formula (VBB) is oxidized by an oxidizing agent to give a compound of the formula (VB); the oxidizing agent is preferably m-chloroperoxybenzoic acid;
    其中:among them:
    R 2、R 4、Z、X和n如权利要求5中所定义。 R 2 , R 4 , Z, X and n are as defined in claim 5.
  14. 一种药用组合物,其包括治疗有效剂量的权利要求1-9任一项所述的化合物以及一种或多种药学上可接受的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a therapeutically effective amount of a compound of any of claims 1-9 and one or more pharmaceutically acceptable carriers, diluents or excipients.
  15. 根据权利要求1-9任一项所述的化合物,或权利要求14所述的药物组合物在制备BRD4抑制剂药物中的应用。Use of a compound according to any one of claims 1-9, or a pharmaceutical composition according to claim 14 for the preparation of a medicament for BRD4 inhibitor.
  16. 根据权利要求1-9任一项所述的化合物,或权利要求14所述的药物组合物在制备治疗癌症、炎症、慢性肝病、糖尿病、心血管疾病和AIDS的药物中的应用。Use of the compound according to any one of claims 1 to 9, or the pharmaceutical composition according to claim 14, for the preparation of a medicament for the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS.
  17. 根据权利要求16所述的应用,其中所述的癌症选自乳腺癌、宫颈癌、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、肝癌、实体瘤、神经胶质瘤、神经胶母细胞瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌;所述的慢性肝病选自:原发性硬化、脑脏性黄瘤症、原发性硬化性胆囊炎、药物导致的胆汁郁积、妊娠肝内胆汁淤积症、肠外吸收相关胆汁郁积、细菌过度生长或脓血症胆汁郁积、自身免疫肝炎、慢性病毒性肝炎、酒精性肝病、非酒精性脂肪肝疾病、非酒精性脂肪性肝炎、肝移植相关移植物抗宿主病、活供体肝移植再生、先天性肝纤维化、胆总管结石、肉芽性肝病、肝内或外恶性肿瘤、Sjogren综合征、结节病、Wilson's疾病、Gaucher's疾病、血色病或α 1一抗膜蛋白酶缺乏症。 The use according to claim 16, wherein said cancer is selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, liver cancer, solid tumor, glioma, and nerve glue. Maternal tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer; said chronic liver disease is selected from the group consisting of: primary sclerosis, cerebral xanthoma, primary sclerosing cholecystitis, drug-induced cholestasis , intrahepatic cholestasis of pregnancy, parenteral absorption-related cholestasis, bacterial overgrowth or sepsis cholestasis, autoimmune hepatitis, chronic viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis , liver graft-related graft-versus-host disease, live donor liver transplant regeneration, congenital liver fibrosis, common bile duct stones, granulomatous liver disease, intrahepatic or extraneous malignancy, Sjogren syndrome, sarcoidosis, Wilson's disease, Gaucher's Disease, hemochromatosis or α 1 -antimembrane protease deficiency.
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